Penicillins

ABSTRACT

Arylmethyl- and cyclohexenylmethyl- penicillins, substituted on the α-carbon atom of the side chain by a 2,3-disubstituted imidazolidinylcarbamide or a 2,3-disubstituted imidazolidinylthiocarbamido group, or by the corresponding 2,3-disubstituted 1,3-diazacyclohexylcarbamido or thiocarbamido groups are anti-bacterial agents.

CROSS REFERENCE

This is a continuation-in-part of our copending applications Ser. Nos.299,264 and 300,776, each of which was filed Oct. 20, 1972 and each ofwhich is now abandoned.

DETAILED DESCRIPTION

The present invention relates to new penicillin compounds, to processesfor their production, to pharmaceutically acceptable compositionswherein such penicillins are the active agent, and to their use in humanand veterinary medicine, as therapeutic agents in poultry and mammals,and as feedstuff additives and as growth-promoting agents in animals.

The new penicillins are valuable as therapeutic agents in poultry andmammals, and in man, in the treatment of infectious diseases caused byGram-positive and Gram-negative bacteria and especially of those causedby bacteria from the group of the enterobacteria and pseudomonades. Thepenicillins of the present invention can be administered orally andparenterally.

Antibacterial agents, such as ampicillin (U.S. Pat. No. 2,985,648) haveproved very effective in the treatment of infections caused byGram-positive and Gram-negative bacteria. However, they are not able tocombat infections which are caused, for example, by bacteria of thegroup of Klebsiella-Aerobacter or by indole-positive strains of Proteus.

Carbenicillin (U.S. Pat. Nos. 3,142,673 and 3,282,926) is only effectivein man in the case of infections caused by Klebsiella-Aerobacter ifadministered in a continuous high dosage, such as is only achieved byinfusion.

The penicillins of the present invention may be regarded asmethylpenicillins which are substituted in the methyl group by a moietyB and an acyl-biureido moiety of which the carbonyl group in the acylgroup can be replaced by a --SO₂ -- group: ##EQU1##

6-(α-Biureido)-acetamido-penicillanic acids are described in U.S. Pat.No. 3,483,188 and in German Offenlegungsschrift No. 1,959,920, but noneof the 6-(α-biureido)-acetamido-penicillanic acids described and claimedin these patents possesses an acyl radical on the nitrogen atom of thebiureido radical which is located in the 5-position.

The present invention comprises new penicillins of the formula ##EQU2##or pharmaceutically acceptable non-toxic salts thereof, wherein ##EQU3##R is straight- chain or branched alkyl of 1 to 5 carbon atoms; R₁ isalkyl preferably of 1 to 10 carbon atoms and especially lower alkyl,cycloalkyl preferably of 3 to 10 carbon atoms, alkenyl preferably of 2to 10 carbon atoms, cycloalkenyl preferably of 3 to 10 carbon atoms,vinyl, arylvinyl, mono-, di- or tri-halo-lower alkyl H₂ N--, R--NH--,(R)₂ N--, aryl-NH--, aryl-lower alkylamino, alkoxy preferably of 1 to 8carbon atoms and especially lower alkoxy, aralkoxy preferably of 1 to 8carbon atoms in the alkoxy portion, cycloalkoxy preferably of 3 to 7carbon atoms, aryloxy preferably of 6 carbon atoms, R--O--V, R--S--V,N.tbd.C--V--, R--O--CO--V--, H₂ N--CO--V--, R--NH--CO--V--,R--O--CO--NH--; R--SO₂ NH--, (R)₂ N--CO--V-- wherein R is as abovedefined, ##SPC1##

provided that when X is --SO₂ --, R₁ is not alkoxy, aralkoxy,cycloalkoxy or aryloxy, and further provided that R₁ can also behydrogen when X is --CO--;

V is a divalent organic radical of 1 to 3 carbon atoms;

n is 0, 1 or 2;

R₂ and R₃ are the same or different and are each hydrogen, alkylpreferably of 1 to 8 carbon atoms and especially lower alkyl, alkenylpreferably of 2 to 8 carbon atoms, vinyl, allyl, propenyl, cycloalkylpreferably of 3 to 6 carbon atoms, cycloalkenyl preferably of 3 to 6carbon atoms, mono-, di- or tri-halo-lower alkyl or aryl;

R₄, r₅ and R₆ are the same or different and are each hydrogen, nitro,cyano, (R)₂ N-- (R)₂ N--CO, R--CO--NH-- R--O--CO--, R--CO--O--, R--,R--O--, wherein R is as above defined, N₂ H--SO₂ --, chlorine, bromine,iodine, fluorine, or trifluoromethyl;

G is hydrogen or straight- or branched-chain alkyl, preferably of 1 to 5carbon atoms;

B is a moiety of the formula ##SPC2##

wherein

R₇, r₈ and R₉ are the same or different and are each hydrogen, halogen,nitro, hydroxy, R--, R--O--, R--S--, R--SO--, R--SO₂ --, (R)₂ N--,R--CO--NH--, or R--CO--O--, wherein R is as above defined.

The terms "lower alkyl" and "lower alkoxy" are intended to be understoodin the present specification as meaning a straight-chain orbranched-chain alkyl or alkoxy group of 1 to 6 carbon atoms. Inconnection with other groups, such as "di-lower alkylamino", the term"lower alkyl" only refers to the alkyl part of the group in question.

The arrow in the divalent linking group Q₂ means that the linkage of twoatoms by the two free valencies of this group must take place asindicated by the arrow.

The present invention includes within its scope penicillins as definedabove in which the chirality center C* is either the R- or the S-configuration, as well as mixtures of the diastereomers resulting fromthe two possible configurations.

According to one preferred embodiment of the present invention, ##SPC3##

The chirality center C* is preferably in the R- configuration.

According to another preferred embodiment of the present invention,##SPC4##

B is phenyl, p-nitrophenyl, p-methylphenyl, p-chlorophenyl,p-hydroxyphenyl, thienyl-(2), ##SPC5##

When the penicillins of the present invention are in the form of apharmaceutically acceptable non-toxic salt, the preferred salts areformed at the carboxylic group and include sodium, potassium, magnesium,calcium, aluminum and ammonium salts, and substituted ammonium saltswith amines, such as di- and tri-lower alkylamines, procaine,dibenzylamine, N,N'-dibenzylethylene-diamine,N-benzyl-β-phenylethylamine, N-methyl- and N-ethyl-morpholine,1-ephenamine, dehydroabietylamine,N,N'-bis-dehydroabietylethylenediamine, and N-lower alkylpiperidine.

The alkali metal salts are particularly preferred, especially the sodiumand potassium salts.

The present invention further provides a process for the production ofthe penicillins of formula I wherein a 6-amino-penicillanic acidderivative of the formula: ##SPC6##

or a product of the condensation of such a derivative with a carbonylcompound, such product having the formula:

or a silyl or disilyl derivative of such derivative, of the formula:##SPC7##

respectively, is reacted with a compound of the formula: ##EQU4##wherein R₁₀, R₁₁ and R₁₂ are the same or different and are each alkyl of1 to 6 carbon atoms; A, B, C*, G, Q₁, Q₂, R₁, R₂, X, Y and Z are asabove defined; and W is halogen, azide or ##EQU5## in an anhydrous oraqueous solvent in the presence of a base, when a compound of theFormula II or III is reacted, or in an anhydrous solvent free ofhydroxyl groups, with or without a base, when a compound of the formulaIV or V is reacted, at a temperature of -50° to +50° C.

The carbonyl compound may, for example, be acetone (see U.S. Pat. No.3,198,804).

If a compound of the formula II or III is used as the starting materialfor the synthesis of the penicillins according to the present invention,and is reacted with a compound of the formula VI, VII, VIII, IX or X,the reaction can be carried out, for example, in a mixture of water andan organic solvent which is miscible with water, such as acetone,tetrahydrofuran, dioxane, acetonitrile, dimethylformamide,dimethylsulphoxide or isopropanol. During the reaction, the pH of thereacting mixture is preferably kept at between 2.0 and 9.0 by additionof a base or the use of a buffer solution. The reaction according to theinvention is however preferably carried out at a pH of between 4.5 and9.0 or between 2.0 and 3.0. It is also possible to carry out thereaction in a water-immiscible solvent, for example in chloroform ormethylene chloride, with the addition of, preferably, triethylamine,diethylamine or N-ethylpiperidine. The reaction can further be carriedout in a mixture of water and a water-immiscible solvent, such as ether,chloroform, methylene chloride, carbon disulphide, isobutyl methylketone, ethyl acetate or benzene, when it is preferred to stir themixture vigorously and to keep the pH at between 4.5 and 9.0 or 2.0 and3.0, by adding a base or using a buffer solution.

If a compound of the formula IV or V is used as the starting materialfor the process of the invention and is reacted with a compound of theformula VI, VII, VIII, IX or X, the reaction must be carried out in ananhydrous solvent free of hydroxyl groups. Examples of suitable solventsare methylene chloride, chloroform, benzene, tetrahydrofurane, acetoneand dimethylformamide. The addition of a base is not necessary, but itcan in some cases improve the yield and purity of the products. Thebase, if added, should generally be either a tertiary amine, such aspyridine or triethylamine, or a secondary amine which as a result ofsteric hindrance is difficult to acylate, such as dicyclohexylamine. Theavailable choice of usable bases is therefore very wide.

As with most chemical reactions, higher or lower temperatures than thoseindicated in the Examples can be used. However, if the parameters givenin the Examples are significantly exceeded, side-reactions willincreasingly take place, which reduce the yield or adversely influencethe purity of the products. On the other hand, excessively loweredreaction temperatures reduce the speed of reaction so greatly thatreductions in yield can arise. Reaction temperatures in the range of-20° C to +50° C are therefore preferred, a temperature of 0° C to + 20°C being particularly preferred.

The reactants can be reacted with one another in equimolecular amounts.It may however be advisable to use one of the two reactants in excess inorder to facilitate the purification, or pure preparation, of thedesired penicillin and to increase the yield. For example, the reactantsof the formula II or III can be employed in an excess of 0.1 to 0.3 molequivalent and as a result a smaller degree of decomposition of thereactants of the formula VI, VII, VIII, IX or X in the aqueous solventmixture can be achieved. The excess of the reactants of the formula IIor III can easily be removed, because of their good solubility inaqueous mineral acid, when working up the reaction mixture. On the otherhand however, it is also possible with advantage to employ the reactantsof the formula VI, VII, VIII, IX or X in an excess of, for example, 0.1to 1.0 mol equivalent. By doing this, the reactants, for example, of theformula II or III, are more economically used and the decomposition ofthe reactants of the formula VI, VII, VIII, IX or X, which takes placeas a side reaction in aqueous solvents, is compensated. Since thecompounds of the formula VI, VII, VIII, IX or X added in excess arerapidly converted, in water, into neutral compounds, which can easily beremoved, the purity of the penicillins is thereby hardly impaired.

The amount of the bases used is determined, for example, by the desiredmaintenance of a particular pH. Where pH measurement and adjustment isnot carried out, or is not possible or meaningful because of the absenceof sufficient amounts of water in the diluent, 2 mol equivalents of baseare preferably added with the compounds of the formula II or III areused, while either no base at all, or, preferably, 1 mol equivalent ofbase is added when the compounds of the formula IV or V are used.

The working up of the reaction batches for the manufacture of thepenicillins according to the present invention, and of their salts, canthroughout be effected in the manner generally known for penicillins.

The free penicillins of the formula I and their salts can beinterconverted in any suitable manner; methods for such interconversionare known.

The compounds of the formula II used as starting materials in theprocess according to the present invention can, as regards theconfiguration of the asymmetric center in the side chain (C*) occur inthe D(-) = R-form or L(+) = S-form. They are described in German PatentSpecification No. 1,156,078, in U.S. Pat. Nos. 3,342,677, 3,157,640,2,985,648 and 3,140,282, in South African Pat. No. 6S/P290 and (ananhydrous form) in U.S. Pat. No. 3,144,445. All crystal forms andconfigurations of the compound of the formula II are suitable as thestarting material for the reaction according to the invention. Thecompounds of the formula III, IV or V used as the starting materials inthe process according to the present invention can, as regards theconfiguration at the asymmetric center in the side chain (C*), alsooccur in the D(-) = R-form or L(+) = S-form. The configuration of theasymmetric centers of the 6-amino-penicillanic acid nucleus in thecompounds of the formula II, III, IV and V should be identical with thecorresponding asymmetric centers of 6-amino-penicillanic acid which hasbeen obtained, for example, from penicillin-G by a fermentative process.

The preparation of the compounds of the formula IV and V used as thestarting material is described in Netherlands Pat. No. 68/16,057.

The preparation of the compounds of the formula VI, VII, VIII, IX or Xused as the starting material in the present invention is illustrated inmore detail in examples.

The penicillins according to the present invention are also produced bythe process of:

i. producing a reactive intermediate by reacting a carboxylic acid ofthe formula XI, a carboxylic acid salt of the formula XIa, or acarboxylic acid silyl or hemisilyl ester of the formula XIb or XIc:##EQU6## in an aqueous or anhydrous organic solvent when a compound ofthe formula XI or XIa is reacted, or in an anhydrous inert organicsolvent free of hydroxy groups when a compound of formula XIb or XIc isreacted, at -70° C to +30° C, with either:

a. a compound of one of the formulae XII to XV ##EQU7## or

b. with a reaction product produced by the reaction of compound of theformula: ##EQU8## with about 1 mol equivalent of thionyl chloride in aninert anhydrous organic solvent in the presence of at least one molequivalent of an organic base acting as an acid-acceptor at atemperature within the range -40° C to +25° C; the reaction productbeing reacted without prior isolation in the presence of a further molequivalent of a base, with about 1 mol equivalent of the carboxylic acidof the formula XI or in the presence of 0-1 mol equivalent of a base,with about 1 mol equivalent of a compound of the formula XIa, XIb orXIc, at a temperature of -40° C to +30° C, whereby the reactiveintermediate produced is of the formula: ##EQU9##

c. [only to be used with carboxylic acids of the formula XI] with about1 mol equivalent of a carbodiimide in a diluent and in the presence ofabout 1 mol equivalent of a compound of the formula XVI whereby thereactive intermediate produced is of the formula: ##EQU10## the diluentbeing anhydrous and free of hydroxy groups if a compound of the formulaXVIII or XIX is to be used in step (ii);

and

ii. reacting the reactive intermediate with 6-aminopenicillanic acid offormula XVIII or silyl- or di-silyl-6-aminopenicillanic acid of theformula XIX or XX. ##EQU11## in a solvent in the presence of a base when6-aminopenicillanic acid is used, or in an anhydrous solvent free ofhydroxy groups when a compound of formula XIX or XX is used, at atemperature in the range of -70° C to + 50° C, to produce the desiredpenicillin compound of the present invention; wherein

A, b, c*, r and Z are as above defined;

Me^(n)(⁺) is a cation of an n-valent alkali metal or alkaline earthmetal or an aluminum cation;

R₁₀, r₁₁ and R₁₂ are as above defined;

R₁₃ is straight- or branched-chain alkyl of 1 to 5 carbon atoms orphenyl;

R₁₄ is --(CH₂)₄ --, --(CH₂)₅ --, or --(CH₂)₂ --O--(CH₂)₂ --;

U which can be the same or different and is --C.tbd.N-- or--CO--O--(lower alkyl); and

W₁ is a halogen atom.

In step (i)(a), the reaction by which the reactive intermediate isproduced is preferably carried out at -50° C to 0° C. Here, and for thesubsequent reaction with the compounds of formula XVIII, XIX or XX, itcan be of advantage if this reaction is allowed to take place in thepresence of about one mol equivalent of an N-hydroxy compound of theformula: ##EQU12## ##SPC8## wherein U is as above defined.

The reaction may be carried out in the presence or absence of a base.

When optical activity is present at the chirality center C*, a possibleracemization at this position can be prevented by using no organicbases, or relatively weak organic bases, for example,N-methylmorpholine, N-ethylmorpholine, N,N-dimethylaniline, pyridine ora weak inorganic base or a buffer, in step (i)(a), (b) and step (ii).

The reactive intermediate produced in step (i) is in all cases, acarboxylic acid of formula XI modified at the carboxyl group.

The reaction in step (ii) is preferably carried out at -50° C to 0° C.It is also preferably carried out in an aqueous solvent at a pH withinthe range 2-9, more preferably within the range 2-3 or 6.5-8.5, when6-aminopenicillanic acid is used.

In the production, according to the invention, of the reactiveintermediate by step (i)(a), from the carboxylic acid of formula XI orits salt of the formula XIa and the compound of the formulae XII, XIII,XIV or XV, anhydrous inert solvents or mixtures of these solvents, suchas tetrahydrofurane, dioxane, dichloromethane, chloroform, ether,benzene, acetone, acetonitrile, dimethylformamide ofhexamethylphosphoric acid triamide are preferably used. However, wateror alcohols such as isopropanol or tert.-butanol can be present if theamounts are not excessive. However, if in this reaction the startingcompounds are the silyl compounds XIb and XIc preferably only thoseorganic solvents are used which contain neither --NH nor --OH groups,for example, dichloromethane, chloroform, tetrahydrofurane, dioxane,diethyl ether, acetonitrile, benzene, acetone and dimethylformamide.

If, in the reaction in step (i)(a) according to the invention betweenthe carboxylic acid of the formula XI, the salt of the formula XIa or asilyl compound of the formula XIb or XIc with the compound of theformula XII, XIII, XIV or XV bases are added, practically all bases aresuitable for this purpose provided they are sufficiently inert towardsacylating agents and provided that when the silyl compounds Vb or Vc areused, they contain no O--H groups, preferably no O--H or N--H groups.

The reactants in the reaction step (i)(a) are preferably reacted withone another in equimolecular amounts. However, it can have aconsiderable influence on the purity of the products or on the yield ifone of the two reactants is used in a more or less large excess.

When converting the carboxylic acids of the formula V into the reactiveintermediate by any of steps o(i)(a), (b) and (c), it is advisible towork at as low a temperature as possible if optical activity present atthe chirality center C* is to be protected against racemization.Temperatures of -40° to -70° C are preferred. For the same reasons it isadvantageous if the reaction time for converting the carboxylic acids ofthe formula XI into the forms modified at the carboxyl group is kept asshort as possible. It can be advisable to maintain conversion times ofonly one minute or a few minutes.

The reaction of step (i)(a) when carried out in the presence of anN-hydroxy compound of the formula XVI, XVIa or XVIb can be carried outin exactly the same way as explained above for step (i)(a) except thatabout one mol equivalent of the N-hydroxy compound is added per mol ofthe compound of the formula XI, XIa, XIb or XIC.

When the reactive intermediate is produced by the method of step (i)(b),the starting material is an N-hydroxy compound of the formula XVI whichis converted, in a solvent such as acetone, tetrahydrofurane, dioxane,dichloromethane, chloroform, benzene, ethyl acetate, diethyl ether ordimethyl formamide, in the presence of at least one mol equivalent of anorganic base, such as triethylamine, pyridine, quinoline,N-methylmorpholine or N,N-dimethylaniline, into a reaction product of(at present) unknown constitution, by reaction with about one molequivalent of thionyl chloride, at a temperature of -40° C. to +25° C.This reaction product is reacted without isolation in the presence of afurther mol equivalent of a base, which may be one of those justmentioned, and preferably in the same amount, with one equivalent of thecarboxylic acid XI, or, without further addition of any base or with upto one mol equivalent of the bases, with one mol equivalent of the saltXIa or the silyl compound XIb or XIc, at a temperature of -40° C to +30°C. The reactive intermediate of the formula XVII can then, optionallyafter removal of the hydrochloride of the base which has been producedduring the reaction and has separated out, be isolated by evaporation ofthe solvent. It may also, if desired, be purified by crystallizationfrom an inert solvent, or, if not crystalline, by brief washing with asolution, for example in ether or benzene, with an aqueous sodiumbicarbonate solution at as low a temperature as possible.

Finally, the reactive intermediate may be produced, according to step(i)(c) of the process of the invention, by reacting the carboxylic acidof the formula XI, in the presence of an N-hydroxy compound of theformula XVI, with a carbodiimide. Suitable carbodiimides include, forexample, dicyclohexylcarbodiimide, diisopropylcarbodiimide andN-ethyl-N'-3-dimethylaminopropylcarbodiimide. They are generally used inan aqueous solvent or solvent mixture, which can contain, for example,acetone, tetrahydrofurane, dioxane, acetonitrole, dimethylformamide,hexamethylphosphoric acid triamide, tertiary-butanol, isopropanol orformic acid methyl ester, or in an anhydrous solvent or solvent mixturewhich in addition to the solvent mentioned can also containdichloromethane, chloroform, ethyl-acetate, ether, benzene, toluene ortetrachloromethane.

In the reaction in step (ii), according to the invention, of6-aminopenicillanic acid (formula XVII) with the reactive intermediate,the 6-aminopenicillanic acid is preferably employed as a solution of itssalt with an acid or a base. Suitable solvents for this purpose are, forexample, water or a mixture of water and one or more water-miscibleorganic solvents, such as tetrahydrofurane, dioxane, acetonitrile,isopropanol, acetone, dimethylformamide, dimethylsulphoxide andhexamethylphosphoric acid triamide. Suitable salt-forming acids are, forexample, hydrochloric acid, sulphuric acid and phosphoric acid. In orderto convert the 6-aminopenicillanic acid into the salt of a base,dissolved in one of the above-mentioned solvents, it is possible to use,as bases suitable for the purpose, for example, inorganic bases such assodium carbonate, sodium hydroxide and sodium bicarbonate, thecorresponding potassium and calcium compounds, calcium oxide, magnesiumoxide, magnesium carbonate or buffer mixtures, and organic bases such asN-methylmorpholine, N-ethylpiperidine, N,N-dimethylaniline, pyridine andtriethylamine. Chloroform or dichloromethane are particularly suitableas solvents for a solution of 6-aminopenicillanic acid in an anhydrousmedium while, for example, triethylamine, diethylamine,N-ethylpiperidine, N-ethylmorpholine and pyridine are suitable as thebase for salt formation. The salts of 6 -aminopenicillanic acid need notbe dissolved completely in the reaction, according to the invention,with the reactive intermediate, but can also be present partly dissolvedand partly in suspension.

Preferred solvents for the reaction between the silyl compounds of6-aminopenicillanic acid, of the formula XVIII or XIX, and the reactiveintermediate, are those which are inert towards silanyl radicals locatedon nitrogen and oxygen. Of these solvents, those preferred are organicsolvents which are free of --NH groups as well as hydroxy groups, forexample, tetrahydrofurane, dioxane, diethyl ether, acetonitrile,benzene, tetrachloromethane, chloroform, dichloromethane,dimethylformamide and acetone. If, in this reaction according to theinvention between the silyl derivative XVIII or XIX of6-aminopenicillanic acid and the reactive intermediate, bases are added,these bases are preferably bases containing neither --NH nor --OHgroups.

In general, the reaction of step (ii) according to the invention betweenthe reactive intermediate and 6-aminopenicillanic acid or its silylderivative XVIII or XIX is carried out using equimolecular amounts ofthe reactants. It can, however, be desirable to use one of the tworeactants in excess in order to facilitate the purification or purepreparation of the desired penicillin compound and to increase theyield. Thus, for example, 6-aminopenicillanic acid or the compound ofthe formula XVIII or XIX can be employed in an excess of 0.1 to 0.4 molequivalent and better utilization of the carboxylic acids of the generalformula V, modified at the carboxyl group, can thereby be achieved.During working up of the reaction mixture and isolation of thepenicillin compound, any 6-aminopenicillanic acid present can easily beremoved because of its good solubility in aqueous mineral acids. On theother hand, any carboxylic acid of the formula XI present is moredifficult to separate from the penicillin formed.

The amount of the base added during the reaction of step (ii), accordingto the invention, of the reactive intermediate, with the6-aminopenicillanic acid or the compound of the formula XVIII or XIX isdetermined, for example, by the desired maintenance of a particular pHvalue. Where a pH measurement and adjustment is not carried out or isnot possible or meaningful because of the absence of sufficient amountsof water in the diluent, up to 2.0 mol equivalents of base are generallyadded when a compound of the formula XVIII or XIX is used, if a base isadded at all, while 1.5 to 2.5 mol equivalents of base are generallyadded when 6-aminopenicillanic acid and an anhydrous reaction medium areused. The amount of the acid added during the reaction in step (ii)according to the invention is also determined, for example, by thedesired maintenance of a particular pH or pH range. In general it isadvantageous to carry out the said reaction between the reactiveintermediate and 6-aminopenicillanic acid or its silyl derivative of theformula XVIII of XIX at temperatures which are as low as possible. As aresult, purer products can be obtained, the yields can be improved andoptical activity present at the chirality center C* can be protectedagainst racemization. However, limits are here imposed by thepossibilities not only of the solubility of the reactants being too lowat lower temperatures, but of crystallization of the solvent beginning.As a result of excessively lowered reaction temperatures, the reactionspeed may be so greatly reduced that the yields may even be lowered. Aswith most chemical reactions, the temperatures used may be lower orhigher than those indicated in the examples. However, if the valuesindicated in the examples are considerably exceeded, side-reactions areto be expected, which reduce the yield and adversely influence thepurity of the products.

The crude products resulting from the process of the invention can beworked up to yield the penicillins of the present invention in themanner conventional in penicillin chemistry.

The free penicillins of the formula I and their salts can beinterconverted in any suitable manner, methods for such interconversionare known in penicillin chemistry.

The 6-aminopenicillanic acid used as the starting material in theprocess of the present invention can be obtained according to knownprocesses by splitting penicillin-G, either by fermentation or bychemical splitting (see Netherlands Pat. No. 67/13,809 and GermanOffenlegungsschrift No. 2,062,925).

The carboxylic acids of the formula XI can be obtained from the aminoacids of the formula: ##EQU13## by reaction with compounds of theformula XXI, XXII, XXIII, XXIV or XXV: ##EQU14## wherein A, B, Q₁, Q₂,R₁, R₂, X, Y, Z, C* and W are as above defined.

The production of the compounds of the formula XXI, XXII, XXIII, XXIVand XXV is in each case described in the individual examples whichfollow.

The production of the compounds of the formula XXII, XIII and XV isdescribed in the literature (see J. Med. Chem. 9 (1966) page 980; Ber.96 (1963) page 2681, Tetrahedron 17 (1962) page 114).

A compound of the formula XIV was obtained fromN,N-dimethylethylenediamine by conversion into theN,N'-bis-trimethylsilyl compound, reaction of the latter with phosgeneto give the corresponding cyclic urea, and reacting the cyclic urea withphosgene.

The penicillins according to the present invention can also be obtainedfrom the carboxylic acids of the formula XI, their salts of the formulaXIa or their silyl compounds XIb and XIc and 6-aminopenicillanic acid orthe silylated 6-aminopenicillanic acids (see formulae XIX and XX) by thecustomary methods of peptide chemistry (see E. Schroder, and K. Lubke,The Peptids, Methods of Peptide Synthesis, Vol. I, pages 76-128).However, the process of the invention has certain advantages over thesecustomary methods.

The antibacterial activity of the new penicillin compounds wasdetermined in vitro and in vivo. Tables 1 to 3 below give the in vitrominimum inhibitory concentration (MIC) in U/ml*) of nutrient medium. Thedetermination was carried out in a liquid medium in the test tube serialdilution test, the reading being taken after 24 hours incubation at 37°C. The MIC is indicated by the non-trubid test tube in the dilutionseries. The growth medium used was a full medium of the followingcomposition:

The numbers here allocated to the penicillin compounds correspond to thenumbers of the Examples in which the particular penicillin is described.

The spectrum of action of the penicillins of the present inventionencompasses both Gram-negative and Gram-positive bacteria. Theparticular advantage of the penicillins according to the presentinvention is that both in vitro and in vivo in animal experiments theyare active against ampicillin- and carbenicilin-resistant bacteria ofthe group Klebsiella-Aerobacter, against ampicillin- andcarbenicillin-resistant indole-positive Proteus and Providenciabacteria, ampicillin- and carbenicillin-resistant Escherichia colistrains, and against ampicillin- and carbenicillin-resistant Pseudomonasaeruginosa and Serratia marcescens bacteria.

The bacteriocidal concentrations required are reached in the serum afterparenteral administration. The results of animal experiments for some ofthe penicillin compounds according to the invention are summarized inTable 3.

The generally excellent action is achieved both on single and onrepeated administration. The penicillins according to the presentinvention are stable to stomach acid. Some of the new penicillins showexcellent toleration, which is made particularly clear by the extremelyhigh dosage which is tolerated, without complications, in the case ofmice when the penicillins are administered intravenously into the veinof the tail. (Table 5)

Table 1 gives a series of minimum inhibitory concentrations ofpenicillin No. 4 (see Example 4a) in comparison with carbenicillin.

                  Table 1                                                         ______________________________________                                                         Minimum inhibitory                                                            concentrations                                                                in μ/ml                                                                      Penicillin Carbeni-                                        Type of Bacteria   No. 4      cillin                                          ______________________________________                                        Pseudomonas                                                                              Bonn        16-32      200                                         aeruginosa Walter      8          100                                                    F 41        25         100                                                    E 27 500    12.5       100                                                    V 10 818    25         100                                                    V 10 797    12.5       50                                                     V 10 887    12.5       100                                                    V 10 900    12.5       50                                                     A           12.5       25                                          Klebsiella-                                                                              60          <0.8       100                                         Aerobacter 62          1.6        100                                                    63           4-16      400                                                    69          1.6        >400                                                   70          3          400                                         Klebsiella-                                                                              1852        >400       >400                                        Aerobacter K 10         4-16      >400                                                   1871        6          400                                                    75          6          >400                                        aerogenes  418         3          400                                         Escherichia                                                                              14          <1         1.6                                         coli       A 261       32-64      400                                                    C 165       1-4        12.5                                                   183/58      1-4        12.5                                                   B           <0.8       --                                                     B 94        <0.8       1.6                                                    55 B 5      <0.8       --                                                     T 7         >400       >400                                                   T 20/2      >400       >400                                                   1465        > 400      >400                                                   26/6        <0.8       3                                                      N           1.6        6                                                      S           32         400                                         Serratia                                                                      marcescens 2           1.6        12.5                                                   3           12.5       400                                                    4           1.6        12.5                                                   6           1.6        12.5                                                   7           1.6        100                                                    9           <0.8       6                                                      13          <0.8       6                                                      K           <0.8       6                                           Providencia                                                                              930         <0.8       6                                                      933         12.5       3                                                      945         <0.8       3                                           Bacillus Proteus                                                              rettgeri   Sp.         0.8        1.6                                                    1 050       >400       >400                                                   824         >400       >400                                        mirabilis  Sp.         1.6        1.6                                                    G.          <0.4       1.6                                                    605         3          400                                                    1 235       1.6        3                                           morganii   Sp.         3          3                                                      932         6          6                                                      1 102       200        >800                                        vulgaris   1 017       1.6        3                                                      3 400       6          50                                          Haemophilus                                                                              2 689       0.25       1.6                                         influenzae 2 718       0.1        0.8                                                    2 786       0.06       1.6                                                    2 788       0.5        <0.4                                                   2 684       0.1        --                                          Strepto-   8 709       12.5       200                                         coccus     8 711       3          50                                          faecalis   8 698       1.6        100                                         Staphylo-  BRL 1 756   200        200                                         coccus     133         1          1                                           aureus     P 209       <0.8       <0.8                                                   SG 511      <0.8       <0.8                                        ______________________________________                                    

Table 2 gives the minimum inhibitory concentrations (MIC values) in U/mlof some penicillins of the present invention, the penicillin numbercorresponding to the example number for a series of types of bacteria:

                                      Table 2                                     __________________________________________________________________________    Type of bacteria                                                              Peni-                                                                              Escherichia coli Prot.                                                                             Prot.                                                                             Psdm. aerug                                                                            Klebsiella                                                                            Staph. aur.                                                                            Strept. faec.         cillin                vulg.                                                                             morg.                                               No.  14  A 261                                                                             C 165                                                                             183/58                                                                             1017                                                                              932 Bonn Walter                                                                            K 10                                                                              63  1756 E                                                                             133 ATCC                  __________________________________________________________________________                                                            9790                  1    <0.8                                                                              400 3   3    6   6   25   50  100 25  400  <0.8                                                                              25                    2    <0.8                                                                              100 1.6 1.6  6   1.6 50   25  50  12.5                                                                              200  <0.8                                                                              50                    3    <1  256 4   4    8   8   16   16  16  16  >256 4   64                    4    <1  32-64                                                                             1-4 1-4  1.6 6   16-32                                                                              8   4-16                                                                              4-16                                                                              64-256                                                                             1   16-32                 5    <1  256 4   4    4   32  32   32  32  16  >256 <1  32                    6    4   >256                                                                              4   4    16  64  32   32  16  32  64   <1  32                    7    <1  >256                                                                              4   <1   16  4   16   8   4   4   128  <1  16                    8    4   >256                                                                              4   4    32  64  32   32  8   32  128  4   128                   9    <1  >256                                                                              4   4    32  32  64   32  4   8   >256 4   128                   10   <1  >256                                                                              4   4    8   4   64   256 8   8   >256 4   128                   11   <1  >256                                                                              4   <1   16  8   32   16  4   4   64   <1  16                    12   <1  64  4   <1   4   8   32*  32  4   8   256  <1  32                    13   <1  128 4   <1   4   <1  16*  16  4   8   128  <1  16                    14   <1  128 4   <1   4   <1  32*  32  4   4   128  <1  32                    19   4   >256                                                                              8   16   16  32  --   --  --  --  --   --  --                    20   4   >256                                                                              8   64   16  8   8*   16  32  64  128  <1  32                    21   <1  256 4   <1   4   4   32*  32  8   8   256  <1  64                    Ampi-                                  100-                                                                              100-                               cillin                                                                             0.8 >400                                                                              6   200  400     200  200 200 200      <1  12.5                  Carbeni-                                                                      cillin                                                                             1.6 400 12.5                                                                              12.5 3   6   200  100 >400                                                                              400 200  1                         22   4   >256                                                                              8   8    16  128 16   32  32  64  128  4   32                    23   <1  128 4   <1   4   <1  16   32  8   8   64   <1  32                    24   <1  512 2   <1   2   2   32   32  4   8   32   <1  16                    25   8   >256                                                                              16  32   16  4   64   32  64  64  64   <1  16                    26   4   >256                                                                              4   4    4   4   32   64  32  16  64   <1  8                     27   0.5 >256                                                                              1   0.5  1   <1  32   32  4   4   64   <0.25                                                                             4                     29   4   >256                                                                              16  32   64  128 16   16  64  64  256  <1  16                    30   <1  >256                                                                              8   64   4   8   32   32  128 64  256  4   128                   31   8   >256                                                                              32  128  >256                                                                              64  256  256 >256                                                                              >256                                                                              64   <1  32                    32   4   >256                                                                              8   8    8   8   256  128 32  16  64   <1  16                    __________________________________________________________________________     *= Pseudomonas aeruginosa F 41.                                          

                                      TABLE 3                                     __________________________________________________________________________    Peni-                                                                             BACTERIA TYPE                                                             cill-                        Pseudomonas       Staphylococcus                                                                          Strept.              in  Escherichia coli Proteus aeruginosa                                                                            Klebsiella                                                                              aureus    faec.                No. 14  A 261                                                                             C 165                                                                              183/58                                                                            vulg.                                                                             morg.                                                                             F41 Walter                                                                            K 10 63   1756 E                                                                             133   ATCC                                     1017                                                                              932                             9790                 __________________________________________________________________________    1   <0.8                                                                               200                                                                              3.1  1.6 3.1 --  50  50  6.2  12.5 400  <0.8 25                   2   <1   256                                                                              4    4   8   8   128 64  32   128  64   <1   64                   3   <1   256                                                                              4    4   4   16  64  64  16   256  128  <1   32                   4   1.6  200                                                                              12.5 6.2 12.5                                                                              --  200 200 50   100  200  <0.8 100                  5   256 ≧256                                                                       ≧256                                                                        256 256 32  ≧256                                                                       ≧256                                                                       ≧256                                                                        >256 ≧256                                                                        4    256                  6   8   >512                                                                              32   16  32  64  256 128 128  256  128  2    128                  7   4    512                                                                              16   8   32  16  128 64  32   128  64   <1   64                   8   2    512                                                                              8    8   16  32  128 64  32   128  ˜64                                                                          <1   64                   9   2    512                                                                              8    8   8   8   64  64  32   128  64   2    64                   10  128 >512                                                                              512  256 256 256 >512                                                                              >512                                                                              >512 >512 512  16   >512                 11  <1   512                                                                              4    2   4   16  64  64  16   16   128  2    64                   13  4   >256                                                                              8    4   16  128 128 128 32   64   256  4    128                  18  1   >256                                                                              8    16  4   <1  256 256 32   32   64   <1   32                   19  4   >256                                                                              8    16  32  4   64  64  32   4    128  <1   32                   20  4   >256                                                                              8    8   8   32  64  32  32   32   64   <1   16                   Ampi-                                                                             0.8 >400                                                                              6    200 400 --  --  200 100-200                                                                            100-200                                                                            --   <1   12.5                 cill-                                                                         in                                                                            __________________________________________________________________________

Tables 1 to 3 indicate the superiority of the in vitro activity ofpenicillins of the present invention as compared to the commerciallyavailable products ampicillin and carbenicillin.

Table 4 shows the effective dose (ED₅₀ - values) in the case of miceinfected intraperitoneally with the bacterium indicated. Thisdemonstrates the superiority of penicillins according to the presentinvention in animal experiments with Gram-negative bacteria as comparedto carbenicillin. Further, Table 4 also shows the good action againstGram-positive bacteria.

                                      Table 4                                     __________________________________________________________________________    Results of animal experiments with white mice for representative              penicillins according to the invention (ED.sub.50 on subcutaneous             treatment, in U/kg)                                                                               Penicillin No.                                            Type of bacteria                                                                          Carbeni-                                                                      cillin  1      2      4                                           __________________________________________________________________________    Klebsiella 63                                                                             >2 × 300,000                                                                    2 × 60,000                                                                     2 × 40,000                                                                     2 × 40,000                            Klebsiella 1871                                                                           >1 × 500,000    1 × 350,000                           Prot. vulg. 1017                                                                          2 × 50,000                                                                             2 × 25,000                                                                     2 × 25,000                            Prot. morg. 932                                                                           2 × 75,000      2 × 75,000                            Psdm. aerug. Walter                                                                       4 × 150,000     4 × 150,000                           Psdm. aerug. F 41                                                                         4 × 100,000     4 × 25,000                                        Propicillin                                                       Staph. aur. 133                                                                           2 × 2,000                                                                       2 × 3,000                                                                      2 × 4,000                                                                      2 × 2,500                             __________________________________________________________________________

Table 5 shows the extremely high level to which some of the penicillinsaccording to the present invention are tolerated, i.e., the relativelylow toxicity of these penicillins.

                  Table 5                                                         ______________________________________                                        Penicillin                                                                            LD.sub.50 on intravenous injection into the vein of                   No.     the tail of mice, in mg/kg                                            ______________________________________                                        2       3,000                                                                 4       3,000                                                                 ______________________________________                                    

The generally excellent antibacterial activity of the presentpenicillins is achieved both on single and on repeated administration.The pencillins according to the present invention are stable to stomachacid. Some of the new pencillins show excellent toleration, which isparticularly made clear by the extremely high dosage which is tolerated,without complications, in the case of mice when administeredintravenously into the vein of the tail.

The present invention also provides a pharmaceutical compositioncontaining as active ingredient a compound of the invention incombination with a pharmaceutically acceptable, non-toxic, inert diluentor carrier.

The invention further provides a pharmaceutical composition containingas active ingredient a compound of the invention in the form of asterile or isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprisinga compound of the invention either alone or in combination with adiluent or carrier.

The invention also provides a medicament in the form of tablets(including lozenges and granules), dragees, capsules, pills, ampoules orsuppositories comprising a compound of the invention either alone or incombination with a suitable diluent or carrier.

"Medicament" as used in this Specification means physically discretecoherent portions suitable for medical administration. "Medicament indosage unit form" as used in this Specification means physicallydiscrete coherent portions suitable for medical administration eachcontaining a daily dose or a multiple (up to four times) or sub-multiple(down to a fortieth) of a daily dose of the compound of the invention.Whether the medicament contains a daily dose or, for example, a half, athird, or a quarter of a daily dose will depend on whether themedicament is to be administered once or, for example, twice, threetimes or four times a day respectively.

The pharmaceutical compositions according to the present invention may,for example, take the form of ointments, gels, pastes, creams, sprays(including aerosols), lotions, suspensions, solutions and emulsions ofthe active ingredient in aqueous or non-aqueous diluents, syrups,granules or powders.

The diluents to be used in pharmaceutical compositions (e.g. granulates)adapted to be formed into tablets, dragees, capsules and pills includethe following: (a) fillers and extenders, e.g. starch, sugars, mannitol,and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose andother cellulose derivatives, alginates, gelatine and polyvinylpyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegratingagents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e)agents for retarding dissolution e.g. paraffin; (f) resorptionaccelerators, e.g. quaternary ammonium compounds; (g) surface activeagents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptivecarriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calciumand magnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills formed from the pharmaceuticalcompositions of the invention can have the customary coatings, envelopesand protective matrices, which may contain opacifiers. They can be soconstituted that they release the active ingredient only or preferablyin a particular part of the intestinal tract, possibly over a period oftime. The coatings, envelopes and protective matrices may be made, forexample, of polymeric substances or waxes.

The ingredients can also be made up in microencapsulated form togetherwith one or several of the above-mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to beformed into suppositories can, for example, be the usual water-solubleor water-insoluble diluents, such as polyethylene glycols and fats (e.g.cocoa oil and high esters [e.g. C₁₄ -alcohol with C₁₆ -fatty acid]) ormixtures of these diluents.

The pharmaceutical compositions which are ointments, pastes, creams andgels can, for example, contain the usual diluents, e.g. animal andvegetable fats, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide or mixtures of these substances.

The pharmaceutical compositions which are powders and sprays can, forexample, contain the usual diluents, e.g. lactose, talc, silicic acid,aluminum hydroxide, calcium silicate, and polyamide powder or mixturesof these substances. Aerosol sprays can, for example, contain the usualpropellants, e.g. chlorofluorohydrocarbons.

The pharmaceutical compositions which are solutions and emulsions can,for example, contain the customary diluents, such as solvents,dissolving agents and emulsifiers; specific examples of such diluentsare water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils [for example, ground nut oil], glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitol or mixtures thereof.

For parenteral administration, the solutions and emulsions should besterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions can contain theusual diluents, such as liquid diluents, e.g. water, ethyl alcohol,propylene glycol, surface-active agents (e.g. ethoxylated isostearylalcohols, polyoxyethylene sorbite and sorbitane esters),microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth or mixture thereof.

All the pharmaceutical compositions according to the present inventioncan also contain coloring agents and preservatives as well as perfumesand flavoring additives (e.g. peppermint oil and eucalyptus oil) andsweetening agents (e.g. saccharin).

The pharmaceutical compositions according to the present inventionpreferably contain about 0.1 to 99.5%, more preferably from about 0.5 to95%, of the active ingredient by weight of the total composition.

In addition to a penicillin of the present invention, the pharmaceuticalcompositions and medicaments according to the invention can also containother pharmaceutically active compounds. They may also contain aplurality of pencillins of the present invention.

The discrete coherent portions constituting the medicament according tothe invention (whether in dosage unit form or not) may be, for example,any of the following: tablets, (including lozenges and granules), pills,dragees, capsules, suppositories and ampoules. Some of these forms maybe made up for delayed release of the active ingredient. Some, such ascapsules, include a protective envelope which renders the portions ofthe medicament physically discrete and coherent.

The preferred daily dose for administration to human subjects of thepenicillins of the present invention is 500,000 to 90,000,000 units ofactive ingredient.

The production of the above-mentioned pharmaceutical compositions andmedicaments is carried out by any method known in the art, for example,by mixing the active ingredient(s) with the diluent(s) to form apharmaceutical composition (e.g. a granulate) and then forming thecomposition into the medicament (e.g. tablets).

This invention further provides a method of combating (including theprevention, relief and cure of) the above-mentioned diseases in humanand non-human animals, which comprises administering to the animals apenicillin of the present invention alone or in combination with asuitable diluent or carrier or in the form of a medicament according tothe present invention.

These aforedisclosed penicillins are suitable for administrationperorally, parenterally (for example intramuscularly, intraperitoneallyor, in particular, intravenously, and intravenously by continuous drip),rectally or topically.

In general it has proved advantageous to administer amounts of from25,000 to 1,000,000 μ/kg of body weight per day to achieve effectiveresults. Nevertheless, it can at times be necesary to deviate from thosedosage rates, and in particular to do so as a function of the nature andbody weight of the human or non-human animal subject to be treated, theindividual reaction of this subject to the treatment, the type offormulation in which the active ingredient is administered and the modein which the administration is carried out. and the point in theprogress of the disease or interval at which it is to be administered.Thus it may in some cases suffice to use less than the above-mentionedminimum dosage rate, while other cases the upper limit mentioned must beexceeded to achieve the desired results. Where larger amounts areadministered it can be advisable to divide these into several individualadministrations over the course of the day.

The present invention also comprises an animal feedstuff comprising apenicillin according to the present invention in combination with anutritious material.

The α-aminobenzylpenicillin used in the Examples contained about 14% ofwater but anhydrous α-aminobenzylpencillins (U.S. Pat. No. 3,144,445)can be employed equally well.

Unless expressly stated otherwise, "ampicillin" is intended to meanα-aminobenzylpenicillin with the D(-)- = R-configuration in theside-chain.

The β-lactam content was determined iodometrically. All penicillinsdescribed herein showed an IR- spectrum corresponding to theirstructure.

The NMR-spectra were recorded in CD₃ OD solution and the signalsindicated in the examples agree with the particular structure; theposition of the signals is given in τ-values.

In calculating the analytical data, the water content is taken intoaccount.

Under the heading: "Activity in animal experiments"; A means that theparticular penicillin, when used subcutaneously in mice againstPseudomonas aeruginosa F 41, is more active than carbenicillin, Bdenotes that it is more active against Klebsiella 63 than carbenicillin,C denotes that is is more active against Klebsiella 63 than cephalothinand D denotes that it is more active against Klebsiella 63 thancephalexin.

The figures (U/ml) quoted in the activities against certain bacteria areminimum inhibitory concentrations in the test tube series dilution testafter 24 hours incubation.

The following non-limitative Examples more particulary illustrate thepresent invention.

EXAMPLE 1 A. SodiumD(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC9##

17.5 parts by weight of ampicillin were suspended in 80% strengthaqueous tetrahydrofurane (140 parts by volume) and sufficienttriethylamine (approx. 6.3 parts by volume) was added dropwise whilestirring, at 20°C, just to produce a clear solution and to give a pHvalue of between 7.5 and 8.2 (glass electrode). The mixture was cooledto 0°C and 7.6 parts by weight of 3-acetyl-imidazolidin-2-on-1-carbonylchloride were added gradually in portions over the course of 30 minutes,while the mixture was stirred and kept at a pH value of between 7 and 8by simultaneous addition of triethylamine. The mixture was stirred for10 minutes at 0°C and subsequently further stirred at room temperatureuntil no further addition of triethylamine was necessary to maintain apH value of 7-8. 150 parts by volume of water were now added and thetetrahydrofurane was largely removed in a rotary evaporator at roomtemperature. The residual aqueous solution was extracted once by shakingwith ethyl acetate, covered with 250 parts by volume of fresh ethylacetate and acidified to pH 1.5-2.0 with dilute hydrochloric acid whilebeing cooled with ice. The organic phase was separated off, washed twicewith 50 parts by volume of water at a time and dried for 1 hour overanhydrous MgSO₄ in a refrigerator. After filtration, about 45 parts byvolume of a 1 molar solution of sodium 2-ethyl-hexanoate in ethercontaining methanol were added to the solution of the penicillin. Themixture was now concentrated on a rotary evaporator until it had an oilyconsistency and was dissolved in a sufficient amount of methanol byvigorous shaking, and the solution was rapidly added dropwise, withvigorous stirring, to 500 parts by volume of ether which contained 10%of methanol. The precipitate was allowed to settle for 30 minutes, thesolution was decanted from the precipitate, and the latter was againsuspended in ether, filtered off and washed with anhydrous ether. Afterdrying over P₂ O₅ in a vacuum dessicator, the sodium salt of thepenicillin was obtained in the form of a white solid substance.

Yield: 95%

β-Lactam content: 84%

Calculated: C, 48.3; H, 4.9; N, 12.8; S, 5.8.

Found: C, 48.6; H(6.2); N, 11.7; S, 5.6.

NMR-signals at τ = 2.3-2.7 (5H), 4.3 (1H), 4.5 (2H), 5.8 (1H), 6.15(4H), 7.5 (3H), 8.4 (3H) and 8.45 ppm (3H).

The product showed only one antibiotically active spot in theelectropherogram.

Activity in animal experiments: B and C

Activity against E. coli 183/58: 3

Activity against Prot. morg. 932: 6

Activity against Psdm. aerug. Bonn: 25

Activity against Klebs. 63 : 25

B. 3-Acetyl-imidazolidin-2-on-1-carbonyl chloride: ##SPC10##

20 parts by weight of N-acetyl-imidazolid-2-one mixed with 25 parts byweight of triethylamine and 150 parts by volume of dry benzene werefirst taken and 27 parts by weight of trimethylchlorosilane in 40 partsby volume of benzene were added dropwise at room temperature over thecourse of 30 minutes, with stirring. The mixture was subsequently boiledfor 18 hours under reflux, moisture being excluded, and thetriethylamine hydrochloride which precipitated (22 parts by weight =100%) was filtered off after cooling and carefully rinsed with drybenzene. The benzene solution thus obtained was treated with a solutionof 17 parts by weight of phosgene in 50 parts by volume of benzene at 5°C and left to stand overnight at 5° C. Thereafter the solvent wasstripped off in vacuo and the residue was dried under an oil pump. Itwas recrystallized from acetone/pentane mixture.

Yield: 81 % Melting point = 104° C

Calculated: C, 37.7; H, 3.7; Cl, 18.6; N, 14.7.

Found: C, 39.3; H, 4.3; Cl, 17.7; N, 14.7.

IR-bands at 1798, 1740, 1690 and 1660 cm.sup.⁻¹.

NMR-signals at τ = 5.65 - 6.3 (4H) and 7.45 ppm (3H)

According to the NMR-spectrum, the product still contained 5-10% ofN-acetyl-imidazolidone, which however does not interfere in the reactionwith ampicillin (Example 1A).

C. N-acetyl-imidazolid-2-one ##SPC11##

23.6 parts by weight of acetyl chloride in 100 parts by volume oftetrahydrofurane were added dropwise over the course of 60 minutes to asuspension of 25.8 parts by weight of imidazol-2-one in 350 parts byvolume of dry tetrahydrofurane at 0° C. The mixture was stirred for 3hours at room temperature, dry air was subsequently blown through thesolution for some time, the solvent was then removed in vacuo and theresidue was recrystallized from boiling nitromethane.

Yield: 52% Melting point = 188° C

Calculated: C, 46.9; H, 6.9; N, 21.9.

Found: C, 47.0; H, 6.2; N, 22.5.

IR-bands at 3230, 1730 and 1640 cm.sup.⁻¹.

NMR-signals at τ = 6.2 (2H), 6.5 (2H) and 7.6 ppm (3H).

EXAMPLE 2 A. SodiumD(-)-α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC12##

This penicillin was produced as described in Example 1A from 6.5 partsby weight of1-(N-methyl-N-trimethylsilyl-amino-carbonyl)-imidazolid-2-one and 14parts by weight of ampicillin.

Yield: 27%

β-Lactam content: 83%

Calculated: C, 46.5; H, 4.9; N, 14.8; S, 5.6.

Found: C, 46.0; H, 5.6; N, 14.0; S, 5.2.

IR-bands at 3330, 1765, 1722, 1672 and 1266 cm.sup.⁻¹.

NMR-signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.55 (2H), 5.85 (1H), 6.25(4H), 7.15 (3H), 8.45 (3H) and 8.5 ppm (3H).

Activity in animal experiments: B, C and D.

Activity against E. coli 183/58: 1.6

Acitivity against Prot. morg. 932: 1.6

Activity against Psdm. aerug. Walter: 25

Activity against Klebsiella 63: 12

B. 3 -(N-methyl-N-trimethylsilyl-aminocarbonyl)-imidazolidin-2-on-1-carbonyl chloride: ##SPC13##

A suspension of 7.1 parts by weight ofN-methylaminocarbonyl-imidazolid-2-one in 150 parts by volume of benzeneand 12 parts by weight of triethylamine was treated dropwise over thecourse of 30 minutes with 13 parts by weight of trimethylchlorosilane,at room temperature, with stirring and the exclusion of moisture, andthe mixture was subsequently kept under reflux for 24 hours. It was thencooled, the triethylamine hydrochloride was filtered off and rinsed withbenzene, and the filtrate was treated with 5 parts by weight of phosgenein 20 parts by volume of benzene. The mixture was left to stand in arefrigerator overnight, the solvent was stripped off in vacuo and theresidue was dried under an oil pump. The residue was suspended in a 1:1mixture of benzene and pentane and filtered off, the filtrate wasevaporated to dryness and the residue was suspended in dry ether andagain filtered off. The filtrate thus obtained was cooled in ice forapproximately 1 hour, the precipitate which formed was again filteredoff and the resulting solution was aevaporated to dryness. Thesemi-solid mass was dried under an oil pump.

According to the NMR-spectrum the substance thus obtained consisted of a3:1 mixture of 1-methylaminocarbonylimidazolid-2-one (NMR-signals at6.1, 6.5 and 7.15 τ) and3-(N-methyl-N-trimethylsilylamino-carbonyl)-imidazolidin-2-on-1-carbonylchloride (NMR-signals at 6.0, 7.0 and 9.7 ppm) which could be reactedwith ampicillin to give the corresponding penicillin (Example 2A).

N-(methylaminocarbonyl)-imidazolidin-2-one: ##SPC14##

14.9 parts by weight of N-chlorocarbonylimidazolidone-2 were added inportions, under cooling with ice, to a solution of 20 parts by weight ofa 50% strength aqueous methylamine solution in 50 parts by weight oftetrahydrofurane which had been adjusted to a pH value of 8.5 withconcentrated hydrochloric acid, and at the same time a pH value of 8.5was maintained by simultaneous addition of triethylamine. Thereafter themixture was further stirred until the pH value had not changed furtherin 15 minutes, even without addition of triethylamine. A pH value of 6.5was established by adding HCl and the tetrahydrofurane was stripped offin vacuo. The product was filtered off, rinsed with a little ice-waterand recrystallized from methanol.

Yield: 72% Melting point = 198° C.

Calculated: C, 41.9; H, 6.3; N, 29.4.

Found: C, 41.7; H, 6.5; N, 30.2.

IR-bands at 3220, 1728 and 1645 cm.sup.⁻¹.

NMR-signals at τ = 2.0 (1H), 2.5 (1H), 6.2 (2H), 6.6 (2H) and 7.2 ppm(3H).

EXAMPLE 3 SodiumD(-)-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC15##

This penicillin was produced as described in Example 1 from 7.8 parts byweight of 3-methoxy-carbonylimidazolidin-2-on-1-carbonyl chloride and17.5 parts by weight of ampicillin.

Yield: 97%

β-Lactam content: 87%

Calculated: C, 48.8; H, 4.4; N, 12.9; S, 5.9.

Found: C, 48.6; H(6.7); N, 11.0; S, 5.5.

IR-bands at 3300, 1775, 1740, 1667, 1605 and 1262 cm.sup.⁻¹.

NMR-signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.15(3H), 6.0-6.3 (4H), 8.4 (3H) and 8.5 ppm (3H).

The product only shows one antibiotically active spot in theelectropherogram.

Activity in animal experiments: B and C.

Activity against E. coli 183/58: 4

Activity against Prot. morg. 932: 8

Activity against Psdm. aerug. Walter: 16

Activity against Klebsiella K 10: 16

B. 3-Methoxycarbonyl-imidazolidin-2-on-1-carbonyl chloride ##SPC16##

This carbamic acid chloride was produced as described in Example 1B from8 parts by weight of N-methoxycarbonyl-imidazolid-2-one, 9.7 parts byweight of trimethylchlorosilane, 9 parts by weight of triethylamine and6.2 parts by weight of phosgene.

Yield: 72%; Melting point = 129° C.

Calculated: C, 34.8; H, 3.4; Cl, 17.2; N, 13.6.

Found: C, 34.8; H, 3.4; Cl, 17.1; N, 13.6.

IR-bands at 1820, 1737, 1690 and 1260 cm.sup.⁻¹.

NMR-signals at τ = 5.7-6.3 (4H) and 6.1 ppm (3H).

C. N-methoxycarbonyl-imidazolid-2-one ##SPC17##

14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one wereintroduced into 70 parts by volume of ice-cold methanol and the mixturewas stirred for 1 hour at room temperature and subsequently for 1 hourat 40°-50° C. After the excess methanol had been stripped off, theresidue was recrystallized from acetone.

Yield: 55% Melting point = 185° C.

Calculated: C, 41.6; H, 5.5; N, 19.4.

Found: C, 41.8; H, 4,8; N, 19.2.

IR-bands at 3320, 1745 and 1670 cm.sup.⁻¹.

EXAMPLE 4 A. SodiumD(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC18##

This pencillin was produced as described in Example 1A from 5.1 parts byweight of 3-methyl-sulphonyl-imidazolidin-2-on-1-carbonyl chloride and9.3 parts by weight of ampicillin.

Yield: >90%

β-Lactam content: 81 %

Calculated: C, 42.7; H, 4.6; N, 11.8; S, 10.8.

Found: C, 42.7; H, 5.4; N, 11.6; S, 11.4.

IR-bands at 3305, 1760, 1728, 1670, 1605, 1360 and 1174 cm.sup.⁻¹.

NMR-signals at τ = 2.3-2.7 (5H), 4.35 (1H), 4.5 (2H), 5.8 (1H), 5.8-6.2(4H), 6.65 (3H), 8.4 (3H) and 8.5 ppm (3H).

Activity in animal experiments: A, B, C and D

Activity against E. coli A 261: 32-64

Activity against E. coli 183/58: 1-4

Activity against Proteus 1017: 1.6

Activity against Psdm. aerug. Walter: 4-16

Activity against Klebsiella K 10: 4-16

B. 1-Chlorocarbonyl-3-methylsulphonyl-imidazolid-2-one: ##SPC19##

16.4 parts by weight of 1-methylsulphonyl-imidazolid- 2-one in dioxanewere boiled for 3 days with 27 parts by weight of trimethylchlorosilaneand 20 parts by weight of triethylamine. The triethylamine hydrochloridewhich precipitated was filtered off, 11 parts by weight of phosgene wereadded to the filtrate and the mixture was left to stand overnight atroom temperature. It was then evaporated to dryness and the residuerecrystallized from boiling acetone.

Yield: 70% Melting point = 178°

Calculated: C, 26.5; H, 3.1; Cl, 15.7; N, 12.4; S, 14.1.

Found: C, 27.2; H, 3.4; Cl, 15.3; N, 12.0; S, 14.1.

NMR-signals at τ= 5.6-6.2 (4H) and 6.6 ppm (3H).

IR-bands at 3010, 1807, 1721, 1360, 1165, 984 and 742 cm⁻ ¹.

The same product can also be manufactured successfully from1-methylsulphonyl-imidazolid-2-one and excess phosgene in methylenechloride.

C. N-methylsulphonyl-imidazolid-2-one: ##SPC20## Instructions 1

63 parts by weight of methane sulphochloride were added dropwise at roomtemperature to a suspension of 43 parts by weight of imidazolidone-2 in400 parts by volume of dry tetrahydrofurane and the mixture was stirredfor 1 hour at 30°-40° C and then heated under reflux for 1 hour.Thereafter the solvent was distilled off in vacuo and the residue waskept under an oil pump for 1 hour at 60° C. The residue wasrecrystallized from warm acetone.

Yield: 25% Melting point: 193° C

Calculated: C, 29.3; H, 4.9; N, 17.1; S, 19.5;

Found: C, 29.0; H, 5.0; N, 17.2; S, 19.6;

IR-bands at 3250, 3115, 1715, 1350 and 1160 cm⁻ ¹.

NMR-signals at τ= 2.4 (1H), 6.2 (2H), 6.5(2H) and 6.8 ppm (3H).

Instructions 2

80 parts be weight of methanesulphochloride followed by 56 parts byweight of triethylamine were added dropwise over the course of 30minutes, while stirring, to a suspension of 43 parts by weight ofimidazolidone-2 in 300 parts by volume of dry tertahydrofurane, in sucha way that the internal temperature was about 35°-40° C. The mixture wasstirred for a further 2 hours at 45° C, the solvent was then strippedoff in vacuo, the residue which remained was extracted twice with 150parts by volume of chloroform at a time, and the crystals which remainedwere recrystallized from methanol.

Yield: 49%. The product agrees, according to melting point and IR-spectrum, with the N-methylsulphonylimidazolid-2-one described above.

EXAMPLE 5 A. SodiumD(-)-α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC21##

16.2 parts by weight of ampicillin in 170 parts by volume of methylenechloride were stirred by 10 parts by weight of triethylamine and 20parts by weight of anhydrous sodium sulphate for 90 minutes at roomtemperature. Thereafter the mixture was filtered and the solution thusobtained was treated, at 0° C, with a suspension of 11 parts by weightof 3-aminocarbonyl-imidazolidin -2-on-1-carbonyl chloride in 30 parts byvolume of methylene chloride. The mixture was stirred for 1 hour at 0° Cand 1 hour at room temperature and poured into 200 parts by volume ofwater, the pH was adjusted to 7 and the methylene chloride was strippedoff in vacuo. The aqueous solution thus obtained was extracted once with100 parts by volume of ethyl acetate, covered with 300 parts by volumeof fresh ethyl acetate and adjusted to pH = 1.5-2.0 with dilutehydrochloric acid, while cooling with ice. The precipitate formed whichwas relatively sparingly soluble in ethyl acetate and consisted of theslightly contaminated free acid of the penicillin, was filtered off andwashed with water. The organic phase was now separated from the water,washed once with water and dried over MgSO₄, and after addition ofsodium 2-ethylhexanoate the penicillin was obtained in the form of itssodium salt, as described in Example 1A.

Yield: 25%

β-Lactam content: 76%

Calculated: C, 45.5; H, 4.7; N, 15.2; S, 5,8.

Found: C, 45.6; H, 6.0; N, 13.7; S, 5.6.

IR-bands at 3300, 1760, 1725, 1670 and 1275 cm⁻ ¹.

NMR-signals at τ= 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.2 (4H),8.4 (3H) and 8.5 ppm (3H).

The free penicillin-acid obtained in 37% yield showed a β-lactam contentof 65% and according to analysis and spectra had the correct structure.

Activity in animal experiments: B, C and D.

Activity against E. coli 183/58: 4

Activity against Proteus 1017: 4

Activity against Psdm. aerug. Walter: 32

Activity against Klebsiella 63: 16

B. 3-Aminocarbonyl-imidazolidin-2-one-1-carbonyl chloride: ##SPC22##

The mixture of 7.7 parts by weight ofN-aminocarbonyl-imidazolidin-2-one, 16.3 parts by weight oftrimethylchlorosilane, 15 parts by weight of triethylamine and 100 partsby volume of benzene was converted, in the manner described in Example2B, firstly into the silyl compound and subsequently, with 6 parts byweight of phosgene, into the carbamic acid chloride.

Yield: 11.6 parts by weight.

IR-bands at 3400, 3300, 2950, 2895, 1795 and 1600 cm⁻ ¹.

C. N-aminocarbonyl-imidazolid-2-one ##SPC23##

29.7 parts by weight of N-chlorocarbonyl-imidazolid-2-one, were reactedat pH = 8.5 and room temperature with 20 parts by volume of 25% strengthaqueous solution of NH₃ in 80% strength aqueous tetrahydrofurane. Afterstripping off the tetrahydrofurane in vacuo, the product whichprecipitated was filtered off and washed with a little ice water. Yieldafter drying over P₂ O₅ in a desiccator: 62%. Melting point 200° C.

Calculated: C, 37.2; H, 5.4; N, 32.6.

Found: C, 37.7; H, 5.3; N, 33.2.

IR-bands at 3345, 3260, 3200, 1740, 1677 and 1590 cm⁻ ¹.

A further 12% of the product were obtainable from the filtrate of themain precipitation, evaporated to dryness, by extracting it by boilingwith several portions of acetone (melting point = 199° C, IR-bands asfor the main amount).

EXAMPLE 6 A. SodiumD(-)-α-[(3-dimethylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC24##

This penicillin was produced as described in Example 1A from 7.1 partsby weight of 3-dimethylaminocarbonyl-imidazolidin-2-on-1-carbonylchloride and 13 parts by weight of ampicillin.

Yield: 76%

β-Lactam content: 93%

Calculated: C, 47.9; H, 5.1; N, 14.6; S, 5.5.

Found: C, 48.1; H, 5.7; N, 14.0; S, 6.1.

IR-bands at 3290, 1760, 1662, 1600 and 1260 cm⁻ ¹.

NMR-signals at τ= 2.4-2.75 (5H), 4.4 (1H), 4.53 (2H), 5.8 (1H), 6.2(4H), 7.0 (6H), 8.43 (3H), and 8.5 ppm (3H).

Activity in animal experiments: B, C and D.

Activity against E. coli 183/58: 4

Activity against Proteus 1017: 16

Activity against Psdm. aerug. Walter: 32

Activity against Klebsiella K 10: 16

B. 3-Dimethylaminocarbonyl-imidazolidin-2-on-1-carbonyl chloride:##SPC25##

This carbamic acid chloride was produced as described in Example 1B from6 parts by weight of N-dimethylamino-carbonyl-imidazolidone-2.Crystalline substance.

Yield: 93%

Calculated: C, 38.3; H, 4.6; Cl, 16.2; N, 19.1.

Found: C, 38.8; H, 5.0; Cl, 16.4; N, (17.3).

IR-bands at 2930, 1800, 1758, 1720 and 1675 cm⁻ ¹.

C. N-dimethylaminocarbonyl-imidazolid-2-one: ##SPC26##

A mixture of 50 parts by volume of a 50% strength aqueous dimethylaminesolution and 70 parts by volume of tetrahydrofurane was adjusted to pH =8 with 5 N hydrochloric acid. 14.9 parts by weight ofN-chlorocarbonyl-imidazolid-2-one were added gradually thereto whilestirring and cooling with ice and the pH value was maintained bysimultaneous addition of further dimethylamine solution. The mixture wasfurther stirred until the pH was constant, the tetrahydrofurane was thenstripped off and the residue was saturated with sodium chloride andrepeatedly extracted with ethyl acetate. The organic solution was washedand saturated sodium chloride solution, dried over MgSO₄ and filtered,and the solvent was evaporated off. The residue was recrystallized fromacetone and dried in a vacuum desiccator over P₂ O₅.

Yield: 36% Melting point = 135° C.

Calculated: C, 45.9; H, 6.4; N, 26.8.

Found: C, 45.9; H, 6.8; N, 27.1.

IR-bands at 3280, 1740, 1715 and 1660 cm⁻ ¹.

EXAMPLE 7 A. SodiumD(-)-α-[(3-i-propyloxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC27##

This penicillin was produced as described in Example 1A from 6.3 partsby weight of 3-(i-propyloxycarbonyl)-imidazolidin- 2-on-1-carbonylchloride and 10.9 parts by weight of ampicillin.

Yield: 62%

β-Lactam content: 85%

Calculated: C, 49.1; H, 5.1; N, 11.9; S, 5.5.

Found: C, 49.2; H, 6.2; N, 11.6; S, 5.6.

IR-bands at 3300, 1765, 1665, 1600 and 1260 cm⁻ ¹.

NMR-signals at τ+ 2.3-2.8 (5H), 4.3 (1H), 4.5 (2H), 4.5-5.1 (1H), 5.8(1H), 6.1 (4H), 8.4 (6H) and 8.6 ppm (6H).

Activity in animal experiments: B, C, and D.

Activity against E. coli 183/58: <1

Activity against Proteus morg. 932: 4

Activity against Psdm. aerug. Walter: 8

Activity against Klebsiella K 10: 4

B. 3-(i-Propyloxycarbonyl)-imidazolidin-2-on-1-carbonyl chloride:##SPC28##

This carbamic acid chloride was produced as described in Example 1B from11 parts by weight of N-i-propyloxycarbonyl-imidazolidone-2, 13.5 partsby weight of trimethylchlorosilane and 7 parts by weight of phosgene.Recrystallization from acetone/pentane.

Yield: 6.8 parts by weight. Melting point = 98°-102° C.

According to the NMR-spectrum and the analysis, the substance consistedof 65% of end product and 35% of starting material, which however didnot interfere with the reaction to give the penicillin.

Calculated for 65% of end product and 35% of starting material:

C, 43.7; H, 5.5; Cl, 9.9; N, 13.5.

Found: C, 44.3; H, 5.5; Cl, 10.1; N, 14.5.

IR-bands at 3220, 1820, 1760, 1940, 1695 and 1685 cm⁻ ¹.

NMR-signals at τ= 4.85, 6.1 and 8.6 ppm (end product) and at τ= 4.9, 6.4and 8.7 ppm (starting material)

C. N-(i-propyloxycarbonyl)-imidazolid-2-one ##SPC29##

14.9 parts by weight of N-chlorocarbonylimidazolid-2-one in 100 parts byvolume of i-propanol and 100 parts by volume of dioxane were warmed to50° C for 3 hours. After stripping off the solvent, the residue wasrecrystallized from acetone.

Yield: 67% Melting point = 86° C

IR-bands at 3320, 1764 and 1670 cm⁻ ¹.

NMR-signals at τ= 5.05 (1H), 5.7-6.75 (5H) and 8.75 ppm (6H).

EXAMPLE 8 A. SodiumD(-)-α-[(3-pyrrolidyl-N-carbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC30##

This penicillin was produced as described in Example 1A from 8 parts byweight of 3-pyrrolidyl-N-carbonyl-imidazolidin-2-on-1-carbonyl chlorideand 13.2 parts by weight of ampicillin.

Yield: 82%

β-Lactam content: 95%

Calculated: C, 49.2; H, 5.3; N, 13.8.

Found: C, 49.3; H (7.1); N, 13.4.

IR-bands at 3290, 1760, 1720, 1655, 1600 and 1250 cm⁻ ¹.

NMR-signals at τ-2.4-2.8 (5H), 4.4 (1H), 4.55 (2H), 5.8 (1H), 6,2 (4H),6.3-6.6 (4H), 7.9-8.3 (4H), 8.45 (3H) and 8.5 ppm (3H).

Activity in animal experiments: A, B and C

Activity against E. coli 183/58: 4

Activity against Proteus 1017: 32

Activity against Psdm. aerug. Walter: 32

Activity against Klebsiella K 10: 8

B. 3-(Pyrrolidyl-N-carbonyl)-imidazolidin-2-on-1-carbonylchloride##SPC31##

This carbamic acid chloride was produced as described in Example 1B from9.2 parts by weight of N-(pyrrolidyl-N-carbonyl)-imidazolidone-2, 13.6parts by weight of trimethylchlorosilane and 5.6 parts by weight ofphosgene. Recrystallization from acetone/ether.

Yield: 1st fraction of melting point = 125° C: 71% 2nd fraction ofmelting point = 120°-122° C: 25%

1st fraction: Calculated - C, 44.0; H, 4.9; Cl, 14.5; N, 17.1.

Found - C, 44.1; H, 5.3; Cl, 15.0; N, 16.8.

IR-bands at 1795, 1755, 1725 and 1660 cm⁻ ¹.

C. N-(pyrrolidyl-N-carbonyl-imidazolid-2-one ##SPC32##

This substance was produced as described in Example 6C fromN-chlorocarbonyl-imidazolidone-2 and pyrrolidine.

Yield: 56% Melting point = 155° C.

Calculated: C, 52.3; H, 7.1 N, 22.9.

Found: C, 51.5; H, 7.0; N, 22.6.

IR-bands at 3240, 1720, 1698, 1647 and 1620 cm⁻ ¹.

NMR-signals at τ= 6.0-6.8 (8H) and 8.0-8.3 (4H).

EXAMPLE 9 A. SodiumD(-)-α-[(3-piperdyl-N-carbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC33##

This penicillin was manufactured in the manner described in Example 1 Afrom 5.0 parts by weight of3-(piperidyl-N-carbonyl)-imidazolidin-2-on-1-carbonyl chloride and 7.6parts by weight of ampicillin.

Yield: 92%

β-Lactam content: 94%

Calculated: C, 51.0; H, 5.4; N, 13.7; S, 5.2.

Found: C, 50.7; H(6.8); N, 13.5; S, 5.7.

IR-bands at 3295, 3050, 1765, 1725, 1667, 1608 and 1265 cm.sup.⁻¹.

NMR-signals at τ = 2.3-2.7 (5H), 4.3 (1H), 4.65 (2H), 5.8 (1H), 6.2(4H), 6.3-6.6 (4H) and 8.1-8.5 ppm (12H).

Activity in animal experiments: B and C

Activity against E. coli 183/58: 4

Activity against Proteus 1017: 32

Activity against Psdm. aerug. Walter: 32

Activity against Klebsiella K 10: 4

B. 3-(Piperidyl-N-carbonyl)-imidazolidin-2-on-1-carbonyl chloride##SPC34##

This carbamic acid chloride was produced as described in Example 1 Bfrom 15.7 parts by weight of N-(piperidyl-N-carbonyl)-imidazolidone-2,21.7 parts by weight of trimethylchlorosilane and 8.4 parts by weight ofphosgene.

Recrystallization from acetone/ether.

Yield: 1st fraction of melting point = 117°C : 27.5%

2nd fraction of melting point = 112°C : 49%

1st fraction:

Calculated: C, 46.3; H, 5.4; Cl 13.7; N, 16.2.

Found: C, 46.3; H, 5.8; Cl 14.6; N, 15.8.

IR-bands at 3060, 1793, 1710, 1659 and 1234 cm.sup.⁻¹.

C. N-(piperidyl-N-carbonyl)-imidazolid-2-one ##SPC35##

This substance was produced as described in Example 6 C fromN-chlorocarbonyl-imidazolid-2-one and piperidine. Recrystallization fromnitromethane.

Yield: 85% Melting point = 187°C

Calculated: C, 54.8; H, 7.6; N, 21.3.

Found: C, 55.2; H, 7.8; N, 20.3.

IR-bands at 3240, 1710, 1675 and 1640 cm.sup.⁻¹.

NMR-signals at τ = 6.0-7.0 (8H) and 8.0-8.6 ppm (6H).

EXAMPLE 10 A. SodiumD(-)-α-[3-phenylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC36##

This penicillin was produced as described in Example 1 A from 2.4 partsby weight of 3-(phenylaminocarbonyl)-imidazolidin-2-on-1-carbonylchloride and 4.4 parts by weight of ampicillin.

Yield: 54%

β-Lactam content: 86%

Calculated: C, 50.9; H, 4.9; N, 13.2; S, 5.0.

Found C, 51.3; H, 5.5 N, 12.2; S, 5.2.

IR-bands at 3390, 3290, 1782, 1720, 1678 and 1598 cm.sup.⁻¹.

NMR-signals a τ = 2.3-3.0 (10H), 4.4 (LH), 4.5 (2H), 5.8 (1H), 6.1 (4H),8.4 (3H) and 8.5 ppm (3H).

Activity in animal experiments: B and C

Activity against E. coli 183/58: 4

Activity against Proteus morg. 932;: 4

Activity against Klebsiella K 10: 8

B. 3-(Phenylaminocarbonyl)-imidazolidin-2-on-1-carbonyl chloride##SPC37##

This carbamic acid chloride was produced as described in Example 1 Bfrom 15.0 parts by weight of N-phenylaminocarbonyl-imidazolid-2-one,15.8 parts by weight of trimethylchlorosilane and 7.2 parts by weight ofphosgene.

Recrystallization from acetone/pentane.

Yield: 12% Melting point = 198°-200°C.

A further precipitate of 8.3 parts by weight was considerably less pure.

IR-bands at 3240, 1785, 1715, 1690 and 1598 cm.sup.⁻¹.

C) N-phenylaminocarbonyl-imidazolid-2-one ##SPC38##

10.2 parts by weight of aniline were first introduced into 120 parts byvolume of 80% strength aqueous tetrahydrofurane at pH = 8 and 14.9 partsby weight of N-chlorocarbonyl-imidazolid-2-one were added in portions atroom temperature while stirring and keeping the pH value at 7-8 bysimultaneous addition of triethylamine. The mixture was further stirreduntil the pH was constant, 80 parts by volume of water were added, thetetrahydrofurane was stripped off in vacuo, the pH was adjusted to 2.5and after standing for one hour in an ice bath the product which hadprecipitated was filtered off. It was washed with ice water and driedover P₂ O₅ in a vacuum desiccator.

Yield: 91% Melting point = 164°C

Recrystallization from acetone gave a product also melting at 164°C, ina yield of 78%.

Calculated: C, 58.5; H, 5.4; N, 20.5.

Found: C, 59.0; H, 5.4; N, 20.7.

IR-bands at 3275, 3090, 1735-1715, 1658, 1616 and 1600 cm.sup.⁻¹.

EXAMPLE 11 A. SodiumD(-)-α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC39##

This penicillin was produced as described in Example 1 A from 5 parts byweight of 3-phenoxycarbonyl-imidazolidin-2-on-1-carbonyl chloride and8.1 parts by weight of ampicillin.

Yield: 42%

β-Lactam content: 88% (determined from thhe analytical Craigdistribution chromatogram)

Calculated: C, 53.7; H, 4.3; N, 11.6; S, 5.3.

Found: C, 53.5; H(5.8); N, 11.1; S, 5.4.

IR-bands at 3300, 3050, 1775, 1740 (shoulder), 1670, 1600 and 1198cm.sup.⁻¹.

NMR-signals at τ = 2.3-2.9 (10H), 4.3 (1H), 4.5 (2H), 5.8 (1H), 6.05Z(4H), 8.4 (3H) and 8.5 ppm (3H).

Activity in animal experiments: B and C

Activity against E. coli 183/58: <1

Activity against Prot. morg. 932: 8

Activity against Psdm. aerug. Walter: 16

Activity against Klebsiella K 10: 4

B. 3-Phenoxycarbonyl-imidazolidin-2-on-1-carbonyl chloride ##SPC40##

This carbamic acid chloride was produced as described in Example 1 Bfrom 11 parts by weight of N-phenoxycarbonyl-imidazolidone-2, 11.7 partsby weight of trimethylchlorosilane and 5.3 parts by weight of phosgene.Recrystallization from acetone/pentane.

Yield: 21% Melting point approx. 130°C

IR-bands at 1780, 1758, 1682 and 1594 cm.sup.⁻¹.

C. N-phenoxycarbonyl-imidazolid-2-on: ##SPC41##

12.7 parts by weight of sodium phenolate were dissolved in 120 parts byvolume of 80% strength tetrahydrofurane and the solution was adjusted topH = 8. 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one werenow introduced while stirring and keeping the pH value constant at 8 bysimultaneous addition of triethylamine. The mixture was further stirreduntil the pH remained constant even without addition of triethylamine.100 parts by volume of water were now added, the tetrahydrofurane wasstripped off in vacuo, the residue was adjusted to pH = 10 with sodiumhydroxide solution, and the solution was extracted with ethyl acetate.The organic solution was washed with water, dried over MgSO₄ andevaporated and the residue was dried under an oil pump at 60°C for 1hour and recrystallized from acetone.

Yield: 56% Melting point = 182°C

Calculated: C, 58.3; H, 4.8; N, 13.6.

Found: C, 58.5; H, 5.1; N. 13.6.

IR-bands at 3260, 3110, 3050, 1780-1760, 1695, 1684, 1597 and 1182cm.sup.⁻¹.

EXAMPLE 12 A. SodiumD(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC42##

This penicillin was produced as described in Example 1 A from 5.5 partsby weight of 3-benzoyl-imidazolidin-2-on-1-carbonyl chloride and 10.1parts by weight of ampicillin.

Yield: 92%

β-Lactam content: 89%

Calculated: C, 49.2; H, 5.2 N, 10.8; S, 4.9.

Found: C, 49.2; H, 5.3; N, 10.8; S, 5.2.

IR-bands at 3220, 3050, 1755, 1725 and 1667 cm.sup.⁻¹.

NMR-signals at τ = 2.2-2.8 (10H), 4.4 (1H), 4.55 (2H), 5.85 (1H), 6.05(4H), 8.4 (3H) and 8.5 ppm (3H).

B. 3-Benzoyl-imidazolidin-2-on-1-carbonyl chloride: ##SPC43##

This carbamic acid chloride was produced as described in Example 1 Bfrom 4.8 parts by weight of N-benzoylimidazolid-2-one, 4.4 parts byweight of trimethylchlorosilane and 2.8 parts by weight of phosgene.

Yield: 100% Melting point = 153°-4°C

Calculated: C, 52.2; H, 3.6; Cl, 14.0; N, 11.1.

Found: C, 51.2; H, 4.4; Cl, 13.2; N, 11.1.

IR-bands at 3060, 1768, 1725 and 1672 and cm.sup.⁻¹.

NMR-signals at τ = 2.5 (5H) and 6.0 ppm (4H).

C. N-benzoyl-imidazolid-2-one ##SPC44##

8.6 parts by weight of imidazolid-2-one in 100 parts by volume of drytetrahydrofurane were treated with 15.5 parts by weight of benzoylchloride in 30 parts by volume of tetrahydrofurane over the course of 15minutes, at 5°-10°C, and the mixture was subsequently stirred for 3hours at 10°C. The solvent was stripped off, the residue was shaken witha mixture of chloroform and aqueous NaHCO₃ solution for 15 minutes, thechloroform was separated off, the water was again extracted withchloroform and the combined organic phases were washed with water, driedover MgSO₄ and evaporated. The residue was recrystallized from ethylacetate/ether.

Yield: 30% Melting point = 169°-70°C

Calculated: C, 63.2; H, 5.3; N, 14.8.

Found: C, 63.0; H, 5.3; N, 14.8.

IR-bands at 3190, 3110, 1742, 1718 and 1655 cm.sup.⁻¹.

NMR-signals at τ = 2.2-2.9 (5H), 3.9 (1H), 6.0 (2H) and 6.6 ppm (2H).

EXAMPLE 13 A. SodiumD(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC45##

The penicillin was produced as described in Example 1 A from 6.0 partsby weight of 3-furoyl(2)-imidazolidin-2-on-1-carbonyl chloride and 12.1parts by weight of ampicillin.

Yield: 90% β-Lactam content: 97%

Calculated: C, 50.0; H, 4.4; N, 11.6; S, 5.3.

Found: C, 49.9; H, 4.9; N, 11.1; S, 6.1.

IR-bands at 3300, 1770 (shoulder), 1740, 1670, 1605 and 1260 cm.sup.⁻¹.

NMR-signals at τ = 2.2 (1H), 2.3-2.8 (6H), 3.4 (1H), 4.35 (1H), 4.55(2H), 5.8 (1H), 6.1 (4H), 8.45 (3H) and 8.5 ppm (3H).

B. 3-Furoyl(2)-imidazolidin-2-on-1-carbonyl chloride ##SPC46##

This carbamic acid chloride was produced as described in Example 1 Bfrom 9 parts by weight of N-furoyl(2)-imidazolid-2-one, 8.7 parts byweight of trimethyl-chlorosilane and 6.0 parts by weight of phosgene.

Recrystallization from benzene.

Yield: 55% Melting point = 119°C

Calculated: C, 44.5; H, 2.9; Cl, 14.6; N, 11.5.

Found: C, 45.0; H, 3.6; Cl, 13.4; N, 11.5.

IR-bands at 3150, 3100, 1800, 1745, 1715, 1650, 1620 and 1255 cm.sup.⁻¹.

NMR-signals at τ = 2.3 (1H), 2.5 (1H), 3.4 (1H) and 5.9 ppm (4H).

C. N-furoyl(2)-imidazolid-2-one ##SPC47##

This substance was produced as described in Example 12 C fromimidazolid-2-one and furane-α-carboxylic acid chloride. Instead ofstirring at 10°C, the mixture was stirred for a further 3 hours at30°-40°C. Recrystallization from nitromethane.

Yield: 53% Melting point = 144°-6°C

Calculated: C, 53.2; H, 4.5; N, 15.6.

Found: C, 51.2; H, 4.5; N, 15.3.

IR-bands at 3245, 3120, 1740, 1622, 1560, 1257 and 1240 cm.sup.⁻¹.

NMR-signals at τ = 2.25 (1H), 2.6 (1H), 3.35 (1H), 6.0 (2H) and 6.4 ppm(2H).

EXAMPLE 14 A. SodiumD(-)-α-[(3-n-butyryl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC48##

This penicillin was produced as described in Example 1 A from 6.0 partsby weight of 3-n-butyryl-imidazolidin-2-on-1-carbonyl chloride and 11.3parts by weight of ampicillin.

Yield: 100%

β-Lactam content: 93.5%.

Calculated: C, 50.5; H, 5.3; N, 12.2; S, 5.6.

Found: C, 50.1; H, 6.0; N, 11.8; S, 6.7.

IR-bands at 3310, 3055, 1760, 1730, 1680, 1603, 1265 and 1230 cm.sup.⁻¹.

NMR-signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.25(4H), 7.1 (2H), 8.2 (2H), 8.4 (3H), 8.5 (3H) and 9.0 ppm (3H).

B. 3-n-Butyryl-imidazolidin-2-on-1-carbonyl chloride ##SPC49##

This carbamic acid chloride was produced as described in Example 1 Bfrom 10.0 parts by weight of N-n-butyryl-imidazolid-2-one, 11.4 parts byweight of trimethylchlorosilane and 7.0 parts by weight of phosgene. Itwas twice recrystallized from acetone/pentane.

Yield: 65% Melting point = 103°C

Calculated: C, 40.2; H, 4.4; Cl, 14.9; N, 11.8;

Found: C, 40.2; H, 4.8; Cl, 14.7; N, 11.7;

IR-bands at 3060, 1792, 1722, 1686 and 1220 cm.sup.⁻¹.

NMR-signals at τ = 6.0 (4H), 7.1 (2H), 8.4 (2H) and 9.0 ppm (3H).

C. N-n-butyryl-imidazolid-2-one ##SPC50##

This substance was produced as described in Example 12 C fromimidazolidone-2 and n-butyryl chloride. Instead of stirring at 10°C, themixture was stirred for a further hour at room temperature and an hourat 50°C. Recrystallize twice from methanol.

Yield: 36% Melting point = 96°C

Calculated: C, 53.9; H, 7.7; N, 18.0.

Found: C, 53.5; H, 7.6; N, 18.3.

IR-bands at 3200, 3120, 1740, 1662 and 1262 cm.sup.⁻¹.

NMR-signals at τ = 6.15 (2H), 6.5 (2H), 7.2 (2H), 8.4 (2H) and 9.1 ppm(3H).

EXAMPLE 15

If, as described in Example 1 A, 0.05 mol of:

3-acetyl-imidazolidin-2-on-1-carbonyl chloride,

3-methylaminocarbonyl-imidazolidin-2-on-1-carbonyl chloride,

3-methoxycarbonyl-imidazolidin-2-on-1-carbonyl chloride,

3-methylsulphonyl-imidazolidin-2-on-1-carbonyl chloride,

3-aminocarbonyl-imidazolidin-2-on-1-carbonyl chloride,

3-phenoxycarbonyl-imidazolidin-2-on-1-carbonyl chloride,

3-furoyl(2)-imidazolidin-2-on-1-carbonyl chloride or3-ethyl-sulphonyl-imidazolidin-2-one-1-carbonyl chloride are reactedwith 0.05 mol of:

α-amino-p-methylbenzylpenicillin,

α-amino-p-methoxybenzylpenicillin,

α-amino-p-methylthiobenzylpenicillin,

α-amino-p-hydroxybenzylpenicillin,

α-amino-p-chlorobenzylpenicillin,

α-amino-p-nitrobenzylpenicillin,

α-amino-α-thienyl(2)-methylpenicillin or

α-amino-α-thienyl(3)-methylpenicillin,

the following penicillins are obtained in the form of their sodiumsalts:

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl-(2)-methylpenicillin,

α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl-(3)-methylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin,

α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,

α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

-[[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin,

α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl(2)-methylpenicillin,

α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl(3)-methylpenicillin,

α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

-[[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin,

α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,

α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,

α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,

α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-hydroxybenzylpenicillin,

α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,

α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,

α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

orα-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin.

EXAMPLE 16

If, as described in Example 1 A, 0.05 mol of:

1-chlorocarbonyl-1,3-dimethyl-3-acetyl-urea,

1-chlorocarbonyl-1,3-dimethyl-3-methylsulphonyl-urea,

1-chlorocarbonyl-1,3-dimethyl-3-methoxycarbonyl-urea,

N-(isothiazolidine-1,1-dioxide-2-yl-carbonyl)-N-methyl-carbamic acidchloride,

1-chlorocarbonyl-3-p-methoxybenzoyl-imidazolidone-(2),

1-chlorocarbonyl-3-methylsulphonyl-4-methyl-imidazolidone-(2),

1-chlorocarbonyl-3-methylsulphonyl-5-methyl-imidazolidone-(2),

1-chlorocarbonyl-1-methyl-3-methylsulphonyl-urea,

1-chlorocarbonyl-1,3-diaza-4-thia-cyclohexan-2-on-4,4-dioxide

or

1-chlorocarbonyl-4-thia-imidazolidin-2-on-4,4-dioxide are reacted with0.05 mol of ampicillin,

the following penicillins are obtained in the form of their sodiumsalts:

D(-)-α-(5-acetyl-3,5-dimethyl-biureido)-benzylpenicillin,

D(-)-α-(5-methylsulphonyl-3,5-dimethyl-biureido)-benzylpenicillin,

D(-)-α-(5-methoxycarbonyl-3,5-dimethyl-biureido)-benzylpenicillin,

D(-)-α-[(3-isothiazolidine-1,1-dioxide-2-yl-carbonyl)-3-methylureido]-benzylpenicillin,

D(-)-α-[(3-(p-methoxybenzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-(p-methylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methyl-5-methylsulphonyl-biureido)-benzylpenicillin,

D(-)-α-(1,3-diaza-4-thia-cyclohexan-2-on-4,4-dioxide-1-yl-carbonylamino)-benzylpenicillinor

D(-)-α-(4-thia-imidazolidin-2-one-4,4-dioxide-1-yl-carbonylamino)-benzylpenicillin.

EXAMPLE 17

If, as described in Example 1A, 0.05 mol of:

N-benzoyl-N-methyl-carbamoylisocyanate,

N-benzoyl-N-methyl-carbamoylisothiocyanate,

N-acetyl-N-methyl-carbamoylisocyanate,

N-acetyl-N-methyl-carbamoylisothiocyanate,

imidazolid-2-on-1-yl-carbonylisocyanate,

imidazolid-2-on-1-yl-carbonylisothiocyanate,

pyrrolid-2-on-1-yl-carbonylisocyanate,

pyrrolid-2-on-1-yl-carbonylisothiocyanate,

1,3,3-trimethyl-ureido-1-carbonylisocyanate,

1,3,3-trimethyl-ureido-1-carbonylisothiocyanate,

N-methylsulphonyl-N-methyl-carbamoylisocyanate,

N-methylsulphonyl-N-methyl-carbamoylisothiocyanate,

1,3-dimethylureido-1-carbonylisocyanate,

1,3-dimethylureido-1-carbonylisothiocyanate,

N-furoyl(2)-N-methylcarbamoylisocyanate,

N-furoyl(2)-N-methylcarbamoylisothiocyanate,

isothiazolidine-1,1-dioxide-2-yl-carbonylisocyanate orisothiazolidine-1,1-dioxide-2-yl-carbonylisothiocyanate are reacted with0.05 mol of ampicillin, the following penicillins are obtained in theform of their sodium salts:

D(-)-α-(5-benzoyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-benzoyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-(5-acetyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-acetyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-[3-imidazolidin-2-on-1-yl-carbonyl)-ureido]-benzylpenicillin,

D(-)-α-[3-(imidazolidin-2-on-1-yl-carbonyl)-thioureido]-benzylpenicillin,

D(-)-α-[3-(pyrrolidin-2-on-1-yl-carbonyl)-ureido]-benzylpenicillin,

D(-)-α-[3-(pyrrolidin-2-on-1-yl-carbonyl)-thioureido]-benzylpenicillin,

D(-)-α-[5-dimethylaminocarbonyl-5-methyl-biureido]-benzylpenicillin,

D(-)-α-[5-dimethylaminocarbonyl-5-methyl-2-thio-biureido]-benzylpenicillin,

D(-)-α-(5-methylsulphonyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-methylsulphonyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-(5-methylaminocarbonyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-methylaminocarbonyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-(5-furoyl(2)-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-furoyl(2)-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-[3-(isothiazolidine-1,1-dioxide-2-yl-carbonyl)-ureido]-benzylpencillinor

D(-)-α-[3-(isothiazolidine-1,1-dioxide-2-yl-carbonyl)-thioureido]-benzylpencillin.

EXAMPLE 18

If, as described in Example 1 A, 0.05 mol of:

1-chlorocarbonyl-3-propionyl-imidazolid-2-one,

1-chlorocarbonyl-3-acetyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-acetyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-acetyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-n-propylsulphonyl-imidazolid-2-one,

1-chlorocarbonyl-3-ethylsulphonyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-ethylsulphonyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-ethylsulphonyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-methylsulphonyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-n-propylsulphonyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-i-propylsulphonyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-i-propylsulphonyl-imidazolid-2-one,

1-chlorocarbonyl-3-i-propylsulphonyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-i-propylsulphonyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-n-propylsulphonyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-n-propylsulphonyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-phenylsulphonyl-imidazolid-2-one,

1-chlorocarbonyl-3-p-methylphenylsulphonyl-imidazolid-2-one,

1-chlorocarbonyl-3-cyclohexylsulphonyl-imidazolid-2-one,

1-chlorocarbonyl-3-thienyl(2)-sulphonyl-imidazolid-2-one,

1-chlorocarbonyl-3-formyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-formyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-formyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-methylaminocarbonyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-methylaminocarbonyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-methylaminocarbonyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-methoxycarbonyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-methoxycarbonyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-methoxycarbonyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-i-propyloxycarbonyl-4-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-i-propyloxycarbonyl-5-methyl-imidazolid-2-one,

1-chlorocarbonyl-3-i-propyloxycarbonyl-1,3-diaza-cyclohexan-2-one,

1-chlorocarbonyl-3-methylsulphonyl-4,5-dimethyl-imidazolid-2-one,

1-chlorocarbonyl-3-methylsulphonyl-4,4-dimethyl-imidazolid-2-one, or

1-chlorocarbonyl-3-methylsulphonyl-5,5-dimethyl-imidazolid-2-one

are reacted with 0.05 mol of ampicillin, the following penicillins areobtained in the form of their sodium salts:

D(-)-α-[(3-propionyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-acetyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-acetyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-acetyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-phenylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-p-methylphenylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-cyclohexylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α[(3-thienyl(2)-sulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylaminocarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylaminocarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylaminocarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methoxycarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methoxycarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methoxycarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propyloxycarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propyloxycarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propyloxycarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-4,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-4,4-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillinor

D(-)-α-[(3-methylsulphonyl-5,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin.

EXAMPLE 19 A. SodiumD(-)-α-[(2-methylsulphonylamino-imidazolin(2)-1-yl)-carbonylamino]-benzylpenicillin:##SPC51##

This penicillin was produced as described in Example 1 A from 4.8 partsby weight of1-chlorocarbonyl-2-methyl-sulphonylamino-4,5-dihydroimidazole and 9parts by weight of ampicillin.

Yield: 38%

β-Lactam content: 96%.

IR-bands at 3060, 1764, 1670, 1605 and 1130 cm.sup.⁻¹.

NMR-signals at τ = 2.3-2.9 (5H), 4.45 (1H), 4.55 (2H), 5.8 (1H), 5.9-6.5(4H), 6.95 (3H), 8.4 (3H) and 8.5 ppm (3H).

Activity against E. coli C 165: 8

Activity against Prot. vulg. 1017: 16

B. 1-Chlorocarbonyl-2-methylsulphonylamino-4,5-dihydroimidazole:##SPC52##

8.2 parts by weight of 2-(N-methylsulphonyl-imino)-imidazoline and 8.0parts by weight of phosgene were reacted in anhydrous dioxane at60°-70°C. The resulting crude product however, on reaction withampicillin, gave the penicillin of the expected structure.

EXAMPLE 20 SodiumD(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC53##

D(-)-α-aminobenzylpenicillin (5.7 parts by weight) was suspended in 80%strength aqueous tetrahydrofurane (60 parts by volume) and sufficienttriethylamine was then added dropwise at 30°C, while stirring, just toproduce a clear solution and to give a pH value of the mixture ofbetween 7.5 and 8.2 (glass electrode). The mixture was then cooled to0°C and a solution of 3-formyl-imidazolidin-2-one-1-carbonyl chloride(2.2 parts by weight) in tetrahydrofurane (20 parts by volume) was addeddropwise. At the same time the pH of the mixture was kept at 7.5 to 8.0by appropriate addition of triethylamine. The mixture was stirred for afurther 30 minutes at 0°C. Thereafter, no further addition oftriethylamine was necessary to maintain the pH value of 7.5 to 8.0.After addition of water (60 parts by volume) the pH was adjusted to 6.5with dilute hydrochloric acid and the tetrahydrofurane was largelyremoved in a rotary evaporator. The aqueous solution which remained wasonce extracted by shaking with ether (the ether extract was discarded)and was subsequently covered with a 1:1 mixture (vol:vol) of ether andethyl acetate and the pH was adjusted to 1-2 by means of dilutehydrochloric acid while stirring and cooling with ice. The organic phasewas then separated off, washed with water, dried for about one hour overmagnesium sulphate at 0°C and, after filtration, diluted with about halfits volume of ether. The sodium salt was then precipitated by adding anapproximate 1 molar solution of sodium 2-ethylhexanoate in ethercontaining methanol. The precipitate was initially oily but could beconverted into an amorphous solid substance after decanting off thesupernatant solution and triturating with ether.

Yield: 0.9 parts by weight (crude product)

β-Lactam content: 77%

According to the NMR-spectrum, the substance contained 3.5 mols of H₂ Oand 0.3 mol of sodium 2-ethylhexanoate per mol. This was taken intoaccount in the calculated values of the analytical data:

Calculated: C, 45.1; H, 5.4; N, 11.2; S, 5.1.

Found: C, 45.2; H, 5.3; N, 11.0; S, 5.3.

NMR-signals at τ = 1.0 (1H), 2.4-2.8 (5H), 4.3-4.6 (3H), 5.8 (1H),6.1-6.3 (4H) and 8.3-8.5 ppm (6H)

Activity against E. coli C 165: 8

Activity against Prot. morg. 932: 8

Activity against Psdm. F 41: 8

Activity against Klebs. K 10: 32

The 3-formyl-imidazolidin-2-on-1-carbonyl chloride used in theproduction of this penicillin was obtained as follows:

N-formyl-imidazolidin-2-one: ##SPC54##

Imidazolidin-2-one (8.6 parts by weight) was suspended intetrahydrofurane (100 parts by volume), formic acid-acetic acidanhydride (10 parts by weight) was added at room temperature whilestirring and thereafter the mixture was stirred at the same temperaturefor 31/4 hours. The precipitate present was filtered off, washed withtetrahydrofurane and dried.

Melting point: 156°-159°C

Calculated: C, 42.1 H, 5.3; N, 24.6.

Found: C, 42.2; H, 5,4; N, 25.3.

NMR-signals at τ = 1.2 (1H) and 5.9 to 6.5 ppm (4H).

3-Formyl-imidazolidin-2-on-1-carbonyl chloride ##SPC55##

A mixture of N-formyl-imidazolidin-2-one (6.0 parts by weight), benzene(40 parts by volume) and triethylamine (11.8 parts by volume) was boiledunder reflux and at the same time a solution of trimethylchlorosilane(8.5 parts by weight) in benzene (20 parts by volume) was addeddropwise. Thereafter the mixture was boiled for a further 5 hours andthen left to stand overnight at room temperature and the precipitatepresent was filtered off and washed with benzene. The combined benzenesolutions, on standing overnight, formed further amounts of precipitatewhich were filtered off. A solution of phosgene (15.6 parts by weight)in dichloromethane (30 parts by volume) was then added dropwise to thefiltrate and the mixture was subsequently left to stand overnight in arefrigerator. It was then completely evaporated to dryness in a rotaryevaporator. The residue, a mass which did not crystallize throughout togive a solid, was used, as it was, for the reaction with ampicillin.

EXAMPLE 21 SodiumD(-)-α-[(3-pivaloyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC56##

This penicillin was produced as described in Example 20 from ampicillin(9.8 parts by weight) and 3-pivaloylimidazolidin-2-on-1-carbonylchloride (4.9 parts by weight)

Yield: 8.6 parts by weight

β-Lactam content: 97.8%

Calculated: C, 50.3; H, 5.6; N, 12.2; S. 5.6.

Found: C, 50.6; H, 5.9; N, 11.6; S, 5.6.

NMR-signals at τ = 2.4-2.8 (5H), 4.3-4.7 (3H), 5.8 (1H), 6.0-6.4 (4H)and 8.3-8.9 ppm (15 H).

Activity against E. coli C 165: 4

Activity against Prot. morg. 932: <1

Activity against Psdm. F 41: 4

Activity against Klebs. K 10: 8

N-pivaloyl-imidazolidin-2-one ##SPC57##

A suspension, cooled to 0°C, of imidazolidin-2-one (17.2 parts byweight) in tetrahydrofurane (200 parts by volume) was treated dropwiseover the course of one hour, with pivaloyl chloride (24.2 parts byweight) at the same temperature. The mixture was then stirred for afurther 3 hours at 0°C, triethylamine (27.8 parts by volume) wassubsequently added dropwise while cooling with ice water, and themixture was then left to stand overnight at room temperature. Thetriethylamine hydrochloride which had separated out was then filteredoff, the filtrate was completely concentrated in vacuo by means of arotary evaporator and the residue was further warmed for 1 hour, invacuo, in a bath at 60°C. The oily product (crude yield: 32.8 parts byweight) was further processed, as it was. When an attempt was made todistill the substance in vacuo, severe decomposition occurred.

3-Pivaloyl-imidazolidin-2-on-1-carbonyl chloride

A solution of trimethylchlorosilane (16.65 parts by weight) in benzene(15 parts by volume) was added dropwise, over the course of one hour, toa boiling mixture if N-pivaloylimidazolidin-2-one (17.5 parts byweight), benzene (100 parts by volume) and triethylamine (23 parts byvolume), the mixture was subsequently boiled for a further 6 hours andthe triethylamine hydrochloride which had separated out was thenfiltered off. The filtrate was combined with a solution of phosgene (13parts by weight) in benzene (20 parts by volume) and the mixture wasthen left to stand overnight at room temperature. The reaction mixturewas then completely evaporated in vacuo and the oily residue was driedin a desiccator over NaOH. Crude yield 22.2 parts by weight. The productwas reacted in this form with ampicillin.

EXAMPLE 22 SodiumD(-)-α-{-[-[3-(ethoxy-carbonyl-amino-sulphonyl)imidazolidin-2-on-1-yl]-carbonylamino-benzylpenicillin:##SPC58##

This penicillin was produced as described in Example 20 from ampicillin(9.8 parts by weight) and3-(ethoxy-carbonyl-trimethylsilylamino)-imidazolidin-2-on-1-carbonylchloride (8.0 parts by weight).

Yield: 2.8 parts by weight

β-Lactam content: 76.8%

NMR-signals at τ = 2.4-2.7 (5H), 6.3-6.7 (3H), 5.8 (1H), 5.85-6.4 (6H),8.3-8.6 (6H) and 8.6-8.95 ppm (3H).

The 3-(ethoxy-carbonyl-trimethylsilylamino)-imidazolidin-2-on-1-carbonylchloride used in the manufacture of this penicillin was obtained asfollows:

3-(Ethoxy-carbonyl-trimethylsilylamino)-imidazolidin-2-on-1-carbonylchloride ##SPC59##

A mixture of the internal salt of ethyl (carboxysulphamoyl)triethylammonium hydroxide (G. M. Atkins, Jr., E. M. Burgers, J. amer.Chem. Soc. 90, 4744 (1968) (12.5 parts by weight) and imidazolidin-2-one(4.0 parts by weight was warmed in a bath at 100° for 2 hours, theresulting thick oil was dissolved in dichloromethane (80 parts byvolume), triethylamine (10.9 parts by volume) was added, this solutionwas then heated to the boil and at the same time a solution oftrimethylchlorosilane (15.8 parts by weight) in benzene (30 parts byvolume) was added dropwise. Thereafter the mixture was boiled underreflux for a further 3 hours. A further 80 parts by volume of benzenewere then added and the mixture was again boiled under reflux for 3hours. After standing overnight at 20°C, solvent was distilled off undernormal pressure up to a boiling point of 70°-75°C, the triethylaminehydrochloride was then filtered off while still hot and after coolingthe filtrate was combined with a solution of phosgene (5.3 parts byweight) in benzene (20 parts by volume). This mixture was left to stand,well sealed, for 24 hours at 20°C. Undissolved material was thenfiltered off and the filtrate was completely evaporated in a rotaryevaporator. An oil remained, which in the IR-spectrum possesses, in thecarbonyl region, a double band with peaks at 1790 and 1730 cm⁻ ¹ (indichloromethane). The substance was used without further purificationfor the reaction with ampicillin.

EXAMPLE 23 SodiumD(=)-α-[(3-cyclohexyloxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC60##

This penicillin was produced as described in Example 20 from ampicillin(6.6 parts by weight) and3-cyclohexyloxy-carbonyl-imidazolidin-2-on-1-carbonyl chloride (4.0parts by weight).

Yield: 1.6 parts by weight

β-Lactam content: 63.7%

Calculated: C, 48.3; H, 5.8; N, 10.5; S, 4.8.

Found: C, 47.5; H, 7.0; N, 10.5; S, 5.1.

NMR-signals at τ = 2.5-2.7 (5H), 4.3-4.7 (3H), 5.8 (1H), 6.0-6.3 (5H)and 8.2-9.2 ppm (16H).

3-Cyclohexyloxycarbonyl-imidazolidin-2-on-1-carbonyl chloride: ##SPC61##

Triethylamine (5.8 parts by weight) was added dropwise to a mixture ofimidazolidin-2-on-1-carbonyl chloride (7.4 parts by weight),tetrahydrofurane (50 parts by volume) and cyclohexanol (5.5 parts byweight) while stirring, and cooling with ice, the mixture was thenslowly stirred overnight at room temperature and subsequently boiled for1 hour uner reflux, and the triethylamine hydrochloride was filtered offhot. The filtrate was completely evaporated in vacuo, the residue wastriturated with cyclohexane and the solid product was filtered off anddried 3 days in a desiccator. Yield: 5.0 parts by weight. This substance(5.0 parts by weight was then suspended in tetrahydrofurane,triethylamine (5.2 parts by volume) was added, the mixture was boiledunder reflux and a solution of trimethylchlorosilane (3.8 parts byweight) in tetrahydrofurane (10 parts by volume) was at the same timeadded dropwise. Thereafter the mixture was boiled overnight under refluxand insoluble matter was then filtered off hot. A solution of phosgene(2.6 parts by weight) in tetrahydrofurane (10parts by volume) was slowlyadded to the filtrate at room temperature and the mixture was left tostand well sealed at room temperature for 24 hours. A precipitate whichwas present (largely triethylamine hydrochloride) was then filtered offand the filtrate was completely evaporated in vacuo. The crystallineresidue was dried in a desiccator. The substance has a broad absorptionbetween 1680 and 1820 cm⁻ ¹ in the carbonyl region of the IR-spectrum(Nujol). It was reacted, in this form, with ampicillin.

EXAMPLE 24 SodiumD(-)-α-[(3-ethanesulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]benzylpenicillin:##SPC62##

This penicillin was produced as described in Example 20 from ampicillin(9.4 parts by weight) and 3-ethanesulphonylimidazolidin-2-on-1-carbonylchloride (5.0 parts by weight).

Yield: 5.7 parts by weight

β-Lactam content: 89.1%

The penicillin contains about 3.3% of sodium 2-ethyl-hexanoate and 6.7%of water. This was taken into account in the calculated values of theanalytical data.

Calculated: C, 43.2; H, 5.1; N, 11.0; S, 10.0;

Found: C, 43.3; H, 5.8; N, 10.8; S, 9.9.

3-Ethanesulphonyl-imidazolidin-2-on-1-carbonyl chloride ##SPC63##

A mixture of imidazolidin-2-one (21.5 parts by weight) andethanesulphonic acid chloride (32.5 parts by weight) was warmed for 4hours in a bath at 150° to 180°. The evolution of HCl had by thenlargely ended. The reaction product was then successively extracted byboiling twice with benzene, twice with acetone and twice with ethylacetate on a water bath and the extracts were decanted. The combinedextracts were completely evaporated in vacuo and the residue wasrecrystallized once from ethyl acetate and once from acetone (in thelatter case with the addition of charcoal powder). Yield: 8.1 parts byweight of N-ethanesulphonylimidazolidin-2-one. Melting point: 114°C.

The N-ethanesulphonyl-imidazolidin-2-one was then suspended indichloromethane, a large excess of phosgene was introduced at 0°C, alittle pyridine was added and the mixture was left to stand overnight.The excess phosgene was then largely removed by passing in dry air andthe product (3-ethanesulphonyl-imidazolidin-2-on-1-carbonyl chloride)was suspended in dichloromethane and filtered off.

Melting point: 174°C.

Calculated: C, 30.0; H, 3.8; Cl, 14.8; N, 11.6; S, 13.3.

Found: C, 30.1; H, 3.8; Cl, 14.7; N, 11.8; S, 13.3.

EXAMPLE 25 A. SodiumD(-)-α-[(2-tosylamino-imidazolin(2)-1-yl)-carbonylamino]-benzylpenicillin:##SPC64##

This penicillin was produced as described in Example 1 A from 7.5 partsby weight of 1-chloro-carbonyl-2-tosylamino-4,5-dihydroimidazole and 11parts by weight of ampicillin.

Yield: 77%

β-Lactam content: 90%

Calculated (the water content of 6.1% was taken into account): C, 47.9;H, 5.0; N, 12.4; S, 9.5. C, 48.3; H, 4.8; N, 10.8; S, 9.1.

IR-bands at 3360- 3200, 1775, 1725, 1675, 1608, 1538, 1290 and 1146 cm⁻¹ (in Nujol).

NMR-signals at τ = 2.2 (2H), 2.4-2.9 (7H), 4.5 (3H), 5.8 (1H), 6.25(4H), 7.6 (3H), 8.4 (3H) and 8.5 ppm (3H).

B. 1-Chlorocarbonyl-2-tosylamino-4,5-dihydro-imidazole ##SPC65##

12 parts by weight of 2-tosylimino-imidazolidine (produced as describedby Gompper and Hagele, Ber. 99, 2892 [1966]) were partly dissolved by 10minutes' boiling in 150 parts by volume of absolute tetrahydrofurane,and thereafter rapidly cooled to 0°C by swirling in an ice bath. 6 partsby weight of phosgene were added to the suspension while stirring, themixture was stirred for 30 minutes at 0°C, 5 parts by weight oftriethylamine were then added dropwise and the whole was then stirredfor a further 3 hours at room temperature. The excess phosgene was blownout by means of a stream of dry air and the precipitated triethylaminehydrochloride was removed from the tetrahydrofurane solution byfiltration and was thoroughly eluted with absolute tetrahydrofurane. Thecombined solutions were evaporated to dryness in vacuo and the residualoil was caused to crystallize by trituration with methylene chloride andether, filtered off and dried in vacuo.

Melting point = 101°C (decomposition ).

Yield: 59%

Calculated: C, 43.8; H, 4.0; Cl, 11.8; N, 13.9; S, 10.6.

Found: C, 43.0; H, 4.3; Cl, 13.5; N, 12.4; S, 10.0.

IR-bands at 3340, 3050, 1796, 1765, 1628, 1265, 1145, 1087 and 905 cm⁻ ¹(in Nujol).

EXAMPLE 26 A. Sodium D(-)-α-[(2-oxo-3-propionyl-1-imidazolidinyl)-carbonylamino]-benzylpenicillin:##SPC66##

This penicillin was produced as described in Example 1 A from 9 parts byweight of 1-chloro-carbonyl-2-oxo-3-propionyl-imidazolidine and 17.5parts by weight of ampicillin.

Yield: 38%

β-Lactam content: 89%

Calculated: (the water content of 2% was taken into account): C, 50.1;H, 5.0; N, 12.7; S, 5.8.

Found: C, 49.8; H, 6.3; N, 12.7; S, 5.6.

IR-bands at 3290, 1760, 1732, 1670, 1603, 1525 and 1250 cm⁻ ¹ (inNujol).

NMR-signals at τ = 2.3-2.8 (5H), 4.35 (1H), 4.5 (2H), 5.8 (1H), 6.0- 6.3(4H), 7.1 (2H), 8.4 (3H), 8.5 (3H) and 8.8 ppm (3H).

B. 1-Chlorocarbonyl-2-oxo-3-propionyl-imidazolidine: ##SPC67##

12 parts by weight of 1-propionyl-2-oxo-imidazolidine, 18.4 parts byweight of trimethylchlorosilane, 15.1 parts by weight of triethylamineand 80 parts by volume of toluene were together kept under refluxovernight, while stirring, and after cooling the precipitate wasfiltered off and eluted with toluene. 9 parts by weight of phosgene wereadded to the combined solutions, the mixture was left to stand overnightat room temperature and then evaporated in vacuo, and the residue wasdried under an oil pump. The product was reacted in this form withampicillin (Example 26 A).

IR-bands at 1822, 1770-1680, 1385 and 1280- 1210 cm⁻ ¹.

C. 1-Propionyl-2-oxo-imidazolidine ##SPC68##

This substance was produced as described in Example 1 C from 17.2 partsby weight of 2-oxo-imidazolidine and 20.4 parts by weight of propionicacid chloridem

Melting point = 147°C (from chloroform).

Yield: 45%

Calculated: C, 50.7; H, 7.0; N, 19.7.

Found: C, 49.2; H, 7.1; N, 20.2.

IR-bands at 3240, 1760- 1736, 1678 and 1280 cm⁻ ¹.

NMR-signals at τ = 3.8 (1H), 6.1 (2H), 6.4 (2H), 7.1 (2H) (in CDCl₃) and8.8 ppm (3H).

EXAMPLE 27 SodiumD(-)-α-[(2-oxo-3-benzenesulphonyl-1-imidazolidinyl)-carbonylamino]-benzylpenicillin:##SPC69##

This penicillin was produced as described in Example 1 A from 5 parts byweight of 1-chloro-carbonyl-2-oxo-3-benzenesulphonyl-imidazolidine and7.5 parts by weight of ampicillin.

Yield: 94%

β-Lactam content: 95%

Calculated (the water content of 3.5% was taken into account): C, 48.0;H, 4.4; N, 10.8; S, 9.9.

Found: C, 48.1; H, 4.6; N, 10.9; S, 10.5.

IR-bands at 3300, 1770, 1740, 1680, 1610, 1530, 1260, 1184 and 1136 cm⁻¹.

NMR-signals at τ = 1.8-2.1 (2H), 2.2-2.8 (8H), 4.4 (1H), 4.5 (2H), 5.8(1H), 6.15 (4H), 8.45 (3H) and 8.5 ppm (3H).

B. 1-Chlorocarbonyl-2-oxo-3-benzenesulphonyl-imidazolidine ##SPC70##

A mixture of 80 parts by weight of1-benzenesulphonyl-2-oxo-imidazolidine, 69 parts by weight of phosgene,31.6 parts by weight of pyridine and 350 parts by volume ofdichloromethane, brought together at 0°C, was stirred overnight at roomtemperature and subsequently evaporated to dryness. Thereafter thematerial was suspended in 500 parts by volume of ice water and filteredoff, the residue was taken up in 500 parts by volume of dichloromethane,the solution was dried over MgSO₄, filtered and again evaporated todryness, and the residue was recrystallized from acetone/petroleumether.

Melting point = 161°C.

Yield: 64%

Calculated: C, 41.6; H, 3.5; Cl, 12.3; N, 9.7; S, 11.1.

Found: C, 41.6; H, 3.0; Cl, 12.2; N, 9.7; S, 10.7.

IR-bands at 1802, 1732, 1318 and 1200 cm⁻ ¹. (in Nujol).

NMR-signals at τ = 1.8-2.1 (2H), 2.1-2.5 (3H) and 5.7-6.1 ppm (4H).

C. 1-Benzenesulphonyl-2-oxo-imidazline: ##SPC71##

86 parts by weight of 2-oxo-imidazolidine, 194 parts by weight ofbenzenesulphonyl chloride, 800 parts by volume of tetrahydrofurane, 500parts by volume of chloroform and 101 parts by weight of triethylaminewere stirred overnight at 50°C and subsequently evaporated to dryness invacuo. The residue was gradually added, while stirring, to 1,000 partsby volume of ice water, the mixture was filtered and the residue wasrecrystallized from ethanol.

Melting point = 155°C.

Yield: 35%

Calculated: C, 47.7; H, 4.4; N, 12.4; S, 14.2.

Found: C, 47.8; H, 4.5; N, 12.2; S, 14.3.

IR-bands at 3280, 1740, 1700, 1280, 1178, 1095 and 1060 cm⁻ ¹ (inNujol).

NMR-signals at τ = 1.8-2.6 (6H), 6.1 (2H) and 6.7 ppm (2H) (in DMSO-d₆).

EXAMPLE 28 SodiumD(-)-α-(4-imino-5-ethoxycarbonyl-biureido)-benzylpenicillin: ##SPC72##

8 parts by weight of 1-(N-nitroso-N-methyl-aminocarbonyl)-3-ethoxycarbonyl-guanidine wereadded in portions, over the course of 15 minutes, to a stirred solutionof 16.3 parts by weight of ampicillin and 5.7 parts by weight oftriethylamine in 100 parts by volume of water. The initially foamingmixture was stirred for 4 hours at room temperature, insoluble matterwas filtered off and the filtrate was covered with 200 parts by volumeof ethyl acetate and acidified to pH = 2 with dilute hydrochloric acid,while cooling with ice. The penicillin was isolated as the sodium saltfrom the ethyl acetate solution of the penicillin-acid, as described inExample 1 A, by precipitation with sodium 2-ethyl-hexanoate solution.

Yield: 15%

β-Lactam content: 66%

IR-bands at 3250, 1760 and 1665 cm⁻ ¹.

NMR-signals at τ = 2.4-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (3H), 8.4 (3H),8.5 (3H) and 8.8 ppm (3H).

B. 1-(N-Nitroso-N-methyl-aminocarbonyl)-3-ethoxycarbonylguanidine:##EQU15##

A solution of 7.3 parts by weight of sodium nitrite in 13 parts byvolume of water was added dropwise over the course of 20 minutes to anice-cooled solution of 11 parts by weight of1-(methylaminocarbonyl)-3-ethoxycarbonyl-guanidine in 58 parts by volumeof 5 N hydrochloric acid. The mixture was stirred for a further hour at0°C and the yellow precipitate formed was filtered off and eluted with alittle ice water.

Yield 8.4 parts by weight. The product, in the moist form, was reactedanalogously to Example 28 A to give the penicillin. A small sample wasdried over P₂ O₅ in vacuo.

Melting point = 116°C (decomposition).

Calculated (a contents of 15% NaCl was taken into account in thecalculation): C, 28.1; H, 4.3; N, 27.4.

Found: C, 27.0; H, 4.3; N, 28.2.

IR-bands at 3400-2400, 1790, 1762 and 1725 cm⁻ ¹.

C. 1-(Methylaminocarbonyl)-3-ethoxycarbonyl-guanidine: ##EQU16##

5.1 parts by weight of methylisocyanate were added to a suspension of 10parts by weight of ethoxycarbonylguanidine (manufactured according toIsr. J. Chem. 8, 651 [1970] ) in 60 parts by volume of anhydrousdioxane, in the course of which the temperature rose to 45°C and theprecipitate dissolved. After a short time, a crystalline precipitateseparated out again, which was filtered off after cooling and washedwith ether. It was dried in vacuo over P₂ O₅ and paraffin chips.

Melting point = 150°C.

Yield: 80%

Calculated: C, 38.2; H, 6.4; N, 29.8.

Found: C, 38.8; H, 6.4; N, 29.1.

IR-bands at 3380, 3300, 1730, 1700-1600, 1580-1520, 1300, 1260 and 1155cm⁻ ¹ (in Nujol).

NMR-signals at τ = 1.0 (3H), 2.8 (1H), 5.95 (2H), 7.3 (3H) (in DMSO-d₆)and 8.8 ppm (3H).

EXAMPLE 29 A. SodiumD(-)-α-3-[N-(1,1-dioxo-isothiazolidin-2-yl)-carbonyl]-3-methyl-ureido-benzylpenicillin:##SPC73##

This pencillin was produced as described in Example 20 from 12.0 partsby weight of ampicillin and 6.3 parts by weight ofN-[(1,1-dioxo-isothiazolidin-2-yl)-carbonyl]-N-methylcarbamic acidchloride. However, when acidifying the penicillin salt solution, it wasacidified to pH 2.0, the solution was at the same time kept at 0°C, andthe solution of the free penicillin-acid in an ether-ethyl acetatemixture was only dried for 15 minute at 0°C over MgSO₄.

Yield: 11.2 parts by weight.

β-Lactam content: about 100%.

Electrophoresis of the penicillin showed that only one antibioticallyactive substance was present.

Specific rotation: [α]₅₈₉ + 141° (methanol/water).

NMR-signals at τ = 2.4-2.8 (5H), 4.3-4.6 (3H), 5.8 (1H), 5.9-6.3 (2H),6.4-6.8 (2H), 6.6 (3H), 7.3-7.7 (2H) and 8.3-8.5 ppm (6H).

B. N-[(1,1-Dioxo-isothiazolidin-2-yl)-carbonyl]-N-methyl-carbamic acidchloride: ##SPC74##

A solution of 7.7 parts by weight of 1,1-dioxo-isothiazolidine and 8.8parts by volume of triethylamine in 30 parts volume of tetrahydrofuranewas added dropwise at room temperature to a solution of 10.0 parts byweight of bis-chlorocarbonyl-methylamine (Farbenfabriken Bayer : GermanOffenlegungschrift No. 1,932,830) in tetrahydrofurane (100 parts byvolume). The mixture was stirred for a further hour to room temperatureand the triethylamine hydrochloride formed was filtered off and washedwith tetrahydrofurane. The combined filtrates were completely evaporatedin vacuo and the residue was recrystallized from hot tetrahydrofuranewith addition of a little pentane.

Yield: 13.1 parts by weight.

Melting point = 102°-103°C.

Calculated: C, 30.0; H, 3.8; Cl, 14.7; N, 11.6; S, 13.3.

Found: C, 30.1; H, 3.9; Cl, 14.3; N, 11.6; S, 13.3.

NMR-signals at τ = 6.15 (triplet) (2H), 6.65 (triplet) (2H), 6.8 (3H)and 7.3-7.9 ppm (multiplet) (2H).

IR-spectrum: 1700 and 1740 cm⁻ ¹ (C = 0).

EXAMPLE 30 A. SodiumD(-)-α-[3-(methylsulphonyl-amino-carbonyl)-imidazolidinon-2-yl-1]-carbonylamino-benzylpenicillin:##SPC75##

This penicillin was produced from 10.0 parts by weight of ampicillin and5.9 parts by weight of3-(methyl-sulphonylamino-carbonyl)-1-chlorocarbonyl-imidazolidinone-(2)as described in Example 20.

Yield: 9.8 parts by weight.

β-Lactam content: 82%

NMR-signals at τ = 2.4-2.8 (5H), 4.3-4.65 (3H), 5.8 (1H), 6.05-6.45(4H), 6.95 (3H) and 8.35-8.75 ppm (6H).

Calculated: *) C, 40.1; H, 5.2; N, 11.7; S, 8.9.

Found: C, 40.4; H, 5.2; N, 11.7; S, 8.8.

On electrophoresis (micro-biological evaluation with Subtilis) thepenicillin shows only one spot.

B. 1-(Methylsulphonyl-amino-carbonyl)-3-chlorocarbonyl-imidazolid-2-one:##SPC76##

7.0 parts by weight of 1-chlorocarbonylimidazolidinone-(2) weredissolved or suspended in 50 parts by volume of tetrahydrofurane, 5.7parts by weight of methanesulphonyl isocyanate were added and themixture was first stirred for 26 hours at room temperature. Sincepractically no reaction had yet occurred at that time, 5 drops ofpyridine were added and the mixture was stirred for a further 65 hoursat room temperature. A crystalline precipitate was then filtered off.

Yield: 10.5 parts by weight.

Melting point = 218°-220°C.

Calculated: C, 26.7; H, 3.0; Cl, 13.1; N, 15.6; S, 11.9.

Found: C, 27.2; H, 3.2; Cl, 12.8; N, 15.5; S, 11.9.

NMR-signals at τ = 5.8-6.2 (multiplet) (4H) and 6.7 ppm (3H).

IR-spectrum: 1800 and 1730 cm⁻ ¹ (C = 0).

EXAMPLE 31 A. Sodium D(-)-α-(5-mesyl-biureido)-benzylpenicillin##SPC77##

This penicillin was produced as described in Example 20 from 11.2 partsby weight of ampicillin and 6.4 parts by weight ofN-mesyl-N'-chlorocarbonyl-urea.

Yield: 3.4 parts by weight.

β-Lactam content: 66.5%.

Calculated: *) C, 39.3; H, 5.1; N, 10.9; S, 10.0.

Found: C, 39.6; H, 6.1; N, 10.2; S, 10.0.

A microbiologically (Bact. Subtilis) developed electropherogram showed,in addition to one large inhibition halo, a second though very smallinhibition halo.

B. N-Mesyl-N'-chlorocarbonyl-urea:

    CH.sub.3 --SO.sub.2 --NH--CO--NH--CO--Cl

6.1 parts by volume of pyridine were added dropwise, while cooling, to amixture of 10.5 parts by weight of N-mesylurea, 60 parts by volume ofdichloromethane and 15.0 parts by weight of phosgene, while cooling, andafter some hours at 0°C the excess of the phosgene was removed, theprecipitate present was filtered off and the filtrate was completelyconcentrated in vacuo. A viscous oil remained, which had an absorptionat 1800 cm⁻ ¹ in the carbonyl region of the IR-spectrum. The substancewas used without further purification for the production of thepenicillin.

EXAMPLE 32 A. Sodium D(-)-α-[(3-methylsulphonyl-4- or5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC78##

This penicillin was produced from 12.0 parts by weight of ampicillin and7.7 parts by weight of 1-methylsulphonyl-3-chlorocarbonyl-4- or-5-methyl-imidazolidin-2-one as described in Example 20.

Yield: 9.3 parts by weight.

β-Lactam content: 94%

Calculated (with 1.33 mol H₂ O): C, 44.0; H, 4.8; N, 11.7; S, 10.7.

Found: C, 44.0; H, 5.0; N, 11.4; S, 10.6.

Specific rotation: [α]₅₈₉ + 135.9° (methanol-water).

NMR-signals at τ = 2.3-2.65 (5H), 4.25-4.6 (3H), 5.75 (1H), 5.8-6.4(3H), 6.6 (3H), 8.3-8.5 (6H) and 8.6-8.8 ppm (3H).

B. 1-Methanesulphonyl-3-chlorocarbonyl-4- or-5-methyl-imidazolidin-2-one ##SPC79##

13.4 parts by weight of 1-methanesulphonyl-4- or -5-imidazolidin-2-onewere added to a solution of 15.0 parts by weight of phosgene in 60 partsby volume of dichloromethane and 6.1 parts by volume of pyridine wereadded dropwise at 0°C. The mixture was then left to stand overnight atroom temperature, phosgene which was still present was removed by meansof a dry stream of air and the solution was then completely concentratedin vacuo. The residue, an oil, was dried in a desiccator over P₂ O₅.

Yield: 27 parts by weight.

IR-bands in the carbonyl region: 1800, 1760 and 1720 cm⁻ ¹.

C. 1-Methanesulphonyl-4- or -5-methyl-imidazolidin-2-one ##SPC80##

A mixture of 53.8 parts by weight of 4-methylimidazolidin-2-one and 64.6parts by weight of methanesulphonic acid chloride was heated in a bathat 90° until the evolution of HCl had ceased (approximately 7 hours).The resulting crude product (yield 34.2 parts by weight) melted at131°-133°. A product of melting point 135°C is obtained byrecrystallization from water on a waterbath.

Calculated: C, 33.7; H, 5.7; N, 15.7; S, 18.0.

Found: C, 33.5; H, 5.5; N, 15.3; S, 18.2.

NMR-signals at τ = 5.9-6.7 (multiplet) (3H), 6.75 (3H) and 8.65 u. 8.75ppm (3H) (doublet).

D. 4-Methylimidazolidin-2-one ##SPC81##

This substance was obtained by heating a mixture of 383 parts by weightof 1,2-diaminopropane and 611 parts by weight of carbonic acid diethylester to 180° in an autoclave for 10 hours and recrystallizing fromisopropanol and methanol.

Yield: 109 parts by weight.

Melting point = 130°C.

EXAMPLE 33 A. SodiumD(-)-α-[3-(thienyl(2)-sulfonyl)-imidazolidin-2-on-1-yl-carbonylamino]-benzylpenicillin:##SPC82##

This penicillin was produced as described in Example 1 A from 3.3 partsby weight of1-chloro-carbonyl-2-oxo-3-(thienyl(2)-sulfonyl)-imidazolidine and 5.0parts by weight of ampicillin.

Yield: 89%.

β-Lactam content: 83%.

Calculated (the water content of 6.4% and the sodium-2-ethylhexanoatecontent of 2.1% were taken into account): C, 43.4; N, 10.2; H, 4.4; S,14.1.

Found: C, 43.7; N, 10.0 H, 4.2; S, 14.1.

IR-bands at 3320, 1770, 1742, 1680, 1610, 1530, 1258 and 1188 cm⁻ ¹.

NMR-signals at τ = 2.0 - 2.2 (2H), 2.4-2.9 (6H), 4.4 (1H), 4.5 (2H), 5.8(1H), 6.2 (4H), 8.45 (3H), and 8.5 ppm (3H).

B. 1-Chlorocarbonyl-2-oxo-3-(thienyl(2)-sulfonyl)-imidazolidine##SPC83##

This carbamic acid chloride was produced as described in Example 27 Bfrom 2.9 parts by weight of 1-thienyl(2)-carbonyl)-2-oxo-imidazolidineand 2.7 parts by weight of phosgene.

Yield: 80%.

Melting point: 166°C.

IR-bands at 3080, 1800, 1728, 1300 and 1178 cm⁻ ¹ (in nujol).

C. 1-(Thienyl(2)-sulfonyl-2-oxo-imidazolidine ##SPC84##

The mixture of 14 parts by weight of 2-chlorosulfonylthiophene and 6.6parts by weight of imidazolidone-2 were heated with stirring to 150°Cuntil the evolution of HCl had finished (ca. 4 hours). After cooling thereaction product was extracted with 150 parts by volume of chloroform/H₂O (2:1), the chloroform-layer was separated, dried over MgSO₄ andevaporated to dryness. The residue was recrystallized from acetone.

Yield: 20.2%.

Melting point = 174°C.

Calculated: C, 36.1; H, 3.5; N, 12.0; S, 27.5.

Found: C, 35.8; H, 3.5; N, 11.9; S, 27.5.

IR-bands at 3230, 3080, 1738, 1705, 1175 and 1062 cm⁻ ¹ (in nujol).

NMR-signals at τ = 2.1-2.4 (2H), 2.8-3.0 (1H), 4.0 (1H), 5.9-6.2 (2H),and 6.3-6.7 ppm (2H) (in CDCl₃).

D. 2-Chlorosulfonyl-thiophene ##SPC85##

This compound was produced as described forchlorosulfonyl-methylthiophene in J. org. Chem. 33, 1357 (1968) fromthiophene, chlorosulfonic acid and PCl₅. The yield was 70%. Thesubstance was a low melting solid.

Boiling point = 117°C (8 mm Hg).

Calculated: C, 26.3; H, 1.6; Cl, 19.4; S, 35.0.

Found: C, 25.9; H, 2.6; Cl, 19.4; S, 34.2.

IR-bands at 3110, 1196, 1032 and 740 cm ⁻ ¹.

NMR-signal at τ = 2.08 (2H) and 2.75 ppm (1H).

EXAMPLE 34 A. Sodium D(-)-α-[(2-oxo-3-acetyl-1,3-diazo-cyclohex-1-yl)-benzylpenicillin ##SPC86##

This penicillin was produced as described in Example 1 A from 7.6 partsby weight of 1-chlorocarbonyl-2-oxo-3-acetyl-1,3-diaza-cyclohexane and16.5 parts by weight of ampicillin.

Yield: 93%.

β-Lactam content: 94%.

Calculated (the water content of 6% was taken into account):

C, 48.1; H, 5.2; N, 12.2; S, 5.5.

Found: C, 48.0; H, 5.5; N, 12.2; S, 6.2.

IR-bands at 3250, 1772, 1700, 1615, 1520, 1305 and 1180 cm⁻ ¹.

NMR-signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.0-6.4(4H), 7.5 (3H), 7.8-8.3 (2H), 8.4 (3H) and 8.5 ppm (3H).

B. 1-Chlorocarbonyl-2-oxo-3-acetyl-1,3-diaza-cyclohexane ##SPC87##

This carbamic acid chloride was produced as described in Example 27 Bfrom 7.1 parts by weight of 1-acetyl-2-oxo-1,3-diaza-cyclohexane and 10parts by weight of phosgene.

Oil. Yield: 89%

Calculated: C, 41.1; H, 4.4; Cl, 17.4; N, 13.7.

Found: C, 41.1; H, 4.5; Cl, 17.1; N, 13.3.

IR-bands at 2950, 1800, 1730, 1706, 1400, 1376, 1320, 1295, 1202, 1178and 1054 cm⁻ ¹.

NMR-signals at τ = 5.9-6.3 (4H), 7.45 (3H) and 7.65-8.15 ppm (2H).

C. 1-Acetyl-2-oxo-1,3-diaza-cyclohexane ##SPC88##

The mixture of 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 11.8parts by weight of acetylchloride, 8.7 parts by weight of pyridine, 50parts by volume of tetrahydrofurane and 50 parts by volume of chloroformwas stirred for 24 hours at room temperature, filtered and washed outwith tetrahydrofurane chloroform (1:1). The combined solutions wereevaporated to dryness, recrystallized from acetone/ethanol; 50 parts byvolume of NaHCO₃ -solution were added, and the mixture was extracted 3times with 50 parts by volume of ethylacetate at a time. The combinedorganic solutions were dried over MgSO₄, evaporated to dryness, and theresidue was recrystallized from acetone/petrol-ether.

Yield: 53%.

Melting point: 132°C.

Calculated: C, 50.7; H, 7.0; N, 19.7.

Found: C, 50.5; H, 7.1; N, 20.1.

IR-bands at 3345, 1708, 1664, 1320, 1281, 1250, 1175, 1130 and 1022 cm⁻¹ (in nujol).

NMR-signals at τ = 6.1-6.4 (2H), 6.6-6.85 (2H), 7.5 (3H) and 7.8-8.3 ppm(2H) (in CD₃ OD).

EXAMPLE 35 A. SodiumD(-)-α-[(3-formyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC89##

This penicillin was produced as described in Example 1 A from 8.1 partsby weight of 1-chlorocarbonyl-2-oxo-3-formyl-1,3-diaza-cyclohexane and18.9 parts by weight of ampicillin.

Yield: 41%.

β-Lactam content: 94%.

Calculated (the water content of 3% was taken into account): C, 48.7; H,4.8; N, 12.9; S, 5.9.

Found: C, 48.4; H, 5.4; N, 11.3; S, 6.5.

IR-bands at 3270, 1765, 1700, 1675, 1603, 1310 and 1183 cm⁻ ¹.

NMR-signals at τ = 0.6 (1H), 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H),6.0-6.5 (4H), 7.75 (2H), 8.4 (3H) and 8.5 ppm (3H).

B. 1-Chlorocarbonyl-2-oxo-3-formyl-1,3-diaza-cyclohexane ##SPC90##

This carbamic acid chloride was produced as described in Example 27 Bfrom 5 parts by weight of 1-formyl-2-oxo-1,3-diaza-cyclohexane and 6parts by weight of phosgene. The substance, an oil, was used withoutfurther purification for the production of the penicillin of Example 35A. IR-bands at 1790, 1685, 1300 and 1165 cm⁻ ¹.

C. 1-Formyl-2-oxo-1,3-diaza-cyclohexane ##SPC91##

The mixture of 10 parts by weight of 1,3-diaza-cyclohexane-2-one, 49parts by weight of trimethylchlorosilane, 25 parts by weight oftriethylamine and 150 parts by volume of dioxane were boiled for 3 dayswith stirring and exclusion of moisture, then filtered, evaporated to 50parts by volume in vacuo and stirred overnight with 11.5 parts by volumeof formic acid-acetic acid anhydride. The mixture was evaporated todryness in vacuo, and the residue was recrystallized from ethanol/ether.

Yield: 40%.

Melting point: 100°C.

Calculated: C, 46.9; H, 6.9; N, 21.9.

Found: C, 46.7; H, 6.3; N, 22.0.

IR-bands at 3250, 3120, 1690, 1312 and 1166 cm⁻ ¹ (in nujol).

EXAMPLE 36 A. SodiumD(-)-α-[(3-mesyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC92##

This penicillin was produced as described in Example 1 A from 5.6 partsby weight of 1-chlorocarbonyl-2-oxo-3-mesyl-1,3-diaza-cyclohexane and 10parts by weight of ampicillin.

Yield: 52%.

β-Lactam content: 94%.

Calculated (the water content of 2.9% and the sodium-2-ethylhexanoatecontent of 2.9% were taken into account): C, 44.8; H, 4.8; N, 11.4; S,10.4.

Found: C, 44.9; H, 5.1; N, 11.0; S, 10.3.

IR-bands at 3300, 1765, 1705-1665, 1605, 1515, 1345 and 1165 cm⁻ ¹.

NMR-signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.0-6.4(4H), 6.6 (3H), 7.7-8.3 (2H), 8.4 (3H) and 8.5 ppm (3H).

B. 1-Chlorocarbonyl-2-oxo-3-mesyl-1,3-diaza-cyclohexane ##SPC93##

This carbamic acid chloride was produced as described in Example 4B from4.5 parts by weight of 1-mesyl-2-oxo-1,3-diaza-cyclohexane, 6.9 parts byweight of trimethyl-chlorosilane and 5.2 parts by weight of phosgene.The oily reaction product was used without further purification for thereaction with ampicillin (Example 36 A).

Yield: 83%.

IR-bands at 2980, 2950, 1790, 1760-1680, 1742, 1355, 1215, 1162, 982 and855 cm⁻ ¹.

C. 1-Mesyl-2-oxo-1,3-diaza-cyclohexane ##SPC94##

This compound was produced as described in Example 35 C from 10 parts byweight of 1,3-diaza-cyclohexan-2-one, 49 parts by weight oftrimethylchlorosilane and 30 parts by weight of mesylchloride. Thereaction product was recrystallized from acetone at low temperature andthereafter from acetone/ethanol.

Yield: 34%.

Melting point: 172°C.

Calculated: C, 33.7; H, 5.6; N, 15.8; S, 18.0.

Found: C, 33.4; H, 5.7; N, 15.6; S, 17.3.

IR-bands at 3210, 3070, 1692, 1340 and 1170 cm⁻ ¹ (in nujol).

NMR-signals at τ = 6.25 (2H), 6.5-6.8 (2H), 6.7 (3H) and 7.8-8.3 ppm(2H) (in CD₃ OD).

EXAMPLE 37 A. SodiumD(-)-α-[(3-phenylsulfonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC95##

This penicillin was produced as described in Example 1 A from 2.6 partsby weight of1-chlorocarbonyl-2-oxo-3-phenylsulfonyl-1,3-diaza-cyclohexane and 3.8parts by weight of ampicillin.

Yield: 82%.

β-Lactam content: 85%.

IR-bands at 3300, 1770, 1695, 1610, 1520 and 1180 cm⁻ ¹.

NMR-signals at τ = 1.9-2.1 (2H), 2.3-2.6 (3H), 2.6 (5H), 4.54 (1H), 4.6(2H), 5.85 (1H), 5.9-6.5 (4H), 7.8-8.25 (2H), 8.47 (3H) and 8.52 ppm(3H).

B. 1-Chlorocarbonyl-2-oxo-3-phenylsulfonyl-1,3-diaza-cyclohexane##SPC96##

This carbamic acid chloride was produced as described in Example 27 Afrom 6 parts by weight of 1-phenylsulfonyl-1,3-diaza-cyclohexane-2-oneand 5 parts by weight of phosgene. The product was recrystallized fromacetone/petrolether.

Yield: 35%.

Melting point: 123°C.

IR-bands at 3350, 1790, 1692 and 1162 cm⁻ ¹ (in nujol).

C. 1-Phenylsulfonyl-2-oxo-1,3-diaza-cyclohexane ##SPC97##

20.4 parts by weight of benzenesulfochloride in 20 parts by volume oftetrahydrofurane were added dropwise at 10°-15°C over the course of 15minutes to a stirred mixture of 10 parts by weight of1,3-diaza-cyclohexane-2-one, 80 parts by volume of tetrahydrofurane and80 parts by volume of chloroform, followed by 10.1 parts by weight oftriethylamine at the same temperature. The mixture was stirred at10°-15°C for 30 minutes and then overnight at 50°C. Subsequently themixture was evaporated to dryness; the residue was stirred with 100parts by volume of water, filtered, stirred with water once more,filtered and washed with ethanol.

Yield: 28%.

Melting point: 207°C.

Calculated: C, 50.0; H, 5.0; N, 11.7; S, 13.3.

Found: C, 49.0; H, 5.0; N, 11.7; S, 12.5.

IR-bands at 3320, 1665, 1348, 1300 and 1175 cm⁻ ¹ (in nujol).

NMR-signals at τ = 1.8-2.2 (2H), 2.3-2.7 (3H), 6.0 (2H), 6.7 (2H) and8.0 ppm (2H) (in CDCl₃).

EXAMPLE 38 SodiumD(-)-α-[(3-methylsulfonyl-imidazolidin-2-on-1-yl-carbonylamino]-1,4-cyclohexadien-yl-1-methylpenicillin##SPC98##

This penicillin was produced as described in Example 20 from 2.5 partsby weight of D(-)-α-Amino-1,4-cyclohexadien-yl 1-methylpenicillin and1.6 parts by weight of1-methylsulfonyl-3-chlorocarbonyl-imidazolidin-2-one.

Yield: 2.6 parts by weight.

β-Lactam content: 93%.

NMR-signals at τ = 4.0 (1H), 4.3 (2H), 4.4 (2H), 4.9 (1H), 5.8 (1H), 6.0(4H), 6.6 (3H), 7.2 (4H) and 8.2-8.4 ppm (6H).

EXAMPLE 39 A. SodiumD(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]benzylpenicillin##SPC99##

6.8 parts by weight ofD(-)-α-[(3-methylsulphonylimidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid were dissolved in 40 parts by volume of methylene chloride with theaddition of a little tetrahydrofurane, the solution was cooled to -40°Cand 2.0 parts by weight of N-methylmorpholine were added with vigorousstirring. Thereafter, a solution of 3.75 parts by weight oftetramethylchloroformamidinium chloride in 15 parts by volume ofmethylene chloride, also cooled to -40°C, was added all at once withvigorous stirring and the mixture was stirred for 5 minutes at -40°C andthen combined with a solution, cooled to 0°C and kept at pH 2.5, of 4.7parts by weight of 6-aminopenicillanic acid in 30 parts by volume of 80%strength aqueous tetrahydrofurane. The pH value of the mixture wasmaintained at 2.5 by addition of further N-methylmorpholine. The mixturewas stirred for 30 minutes without cooling, while the pH was maintainedat 2.5. Thereafter, 40 parts by volume of water were added, the pH valuewas then adjusted to 7, methylene chloride and tetrahydrofurane werestripped off on a rotary evaporator, the solution was extracted oncewith 50 parts by volume of ethyl acetate and the aqueous phase wascovered with fresh ethyl acetate. The mixture was acidified with dilutehydrochloric acid to pH = 1.5 under stirring and cooling with ice, theethyl acetate was separated off, the aqueous phase was extracted twicemore with ethyl acetate and the combined organic phases were washed withwater and dried over MgSO₄. Thereafter they were filtered, 20 parts byvolume of a molar solution of sodium 2-ethylhexanoate in ethercontaining methanol were added, the mixture was evaporated practicallyto dryness in vacuo, the residue was dissolved in the minimum possibleamount of methanol and the sodium salt of the penicillin wasprecipitated by adding a tenfold amount of absolute ether with shaking.It was filtered off, thoroughly washed with absolute ether and driedover P₂ O₅ in a vacuum dessicator.

Yield: 84%

β-Lactam content: 74%.

Calculated: C, 43.4; H, 4.8; N, 11.3; S, 10.4.

Found: C, 43.4; H, 5.4; N, 11.3; S, 10.3.

IR-bands at 3325, 3055, 3025, 3002, 2965, 2924, 2865, 1771, 1738, 1679,1610, 1529, 1398 and 1171 cm⁻ ¹.

NMR-signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8(1H), 6.15 (4H),8.4 (3H) and 8.5 ppm (3H).

B.1.D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid: ##SPC100##

16.6 parts by weight of D(-)-C-phenylglycine were dissolved in 150 partsby volume of 50% strength aqueous dioxane with addition of a sufficientamount of 2N sodium hydroxide solution. The pH of the solution was nowreduced to 7.5 by adding 2 N hydrochloric acid, whereupon the aminoacidpartially separated out again in a finely divided form.1-Chlorocarbonyl-3-methylsulphonyl-imidazolid-2-one was now added inportions under cooling with ie and the pH of 7.5 was maintained bysimultaneously adding 2 N sodium hydroxide solution. The mixture wasfurther stirred, without cooling, until the pH-value remained constantat 7.5 even without addition of sodium hydroxide solution (about 10minutes). Thereafter, 50 parts by volume of water were added, themixture was evaporated on a rotary evaporator to half the originalvolume and the residue was extracted once with 50 parts by volume ofethyl acetate, after unreacted C-phenylglycine had been filtered off.Thereafter the mixture was acidified to pH = 2 and repeatedly extractedwith ethyl acetate. The combined ethyl acetate phases were washed withwater, dried over MgSO₄, filtered, evaporated to dryness andrecrystallized from acetone/nitromethane. Melting point = 250° C.

Yield: 56%.

Calculated: C, 45.7; H, 4.4; N, 12.3; S, 9.4.

Found: C,45.7; H, 4.5; N, 12.3; S, 9.2.

IR-bands at 3345, 3600, -2300, 1731, 1652, 1538, 1210 and 1168 cm⁻ ¹ (inNujol).

NMR-signals at τ = 1.2 (1H), 2.55 (5H), 4.6 (1H), 6.2 (4H) and 6.6 ppm(3H).

2.D,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)carbonylamino]-4-chloro-phenylaceticacid ##SPC101##

This carboxylic acid was produced as described in Example 39 B 1 from5.8 parts by weight of 4-chloro-C-phenylglycine and 6.8 parts by weightof 1-chlorocarbonyl-3-methylsulphonyl-imidazolid-2-one.

Melting point = 190° C.

Yield: 88%.

Calculated: C, 41.6; H, 3.7; Cl, 9.4; N, 11.2; S, 8.5.

Found: C, 40.8; H, 3.7; Cl, 9.2; N, 11.1; S,8.9.

IR-bands at 3700-2200, 3310, 1730, 1654, 1540 and 1168 cm⁻ ¹ (in Nujol).

NMR-signals at τ = 1.1 (1H), 2.55 (4H), 4.5 (1H), 6.1 (4H) and 6.65 ppm(3H).

3.D,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)carbonylamino]-.alpha.-thienyl-(2)-aceticacid ##SPC102##

This carboxylic acid was produced as described in Example 39B.1 from 5.5parts by weight of α-thienyl-(2)-glycine and 6.8 parts by weight of1-chloro-carbonyl-3-methylsulphonylimidazolid-2-one.

Yield: 88%.

Melting point approx: 110° C, crude product.

Calculated: C, 38.0; H, 3.8; N, 12.1; S, 18.4.

Found: C, 38.2; H, 4.8; N, 10.8; S, 17.0.

IR-bands at 3600-2200, 3315, 1740, 1725, 1664, 1525 and 1170 cm⁻ ¹ (inNujol).

NMR-signals at τ = 1.2 (1H), 2.4-3.1 (3H), 4.2 (1H), 6.07 (4H) and 6.67ppm (3H).

4.L(+)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid ##SPC103##

This carboxylic acid was produced as described in Example 39 B.1 from5.3 parts by weight of L(+)-C-phenylglycine and 6.8 parts by weight of1-chlorocarbonyl-3-methylsulphonyl-imidazolid-2-one.

Melting-point +245° C

Calculated: C, 45.7; H, 4.4; N, 12.3; S, 9.4.

Found: C, 44.9; H, 4.5; N, 11.9; S, 9.4.

The IR- and NMR-spectra are identical with those of the product fromExample 39 B.1.

5. D,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-2,6-dichlorophenylacetic acid ##SPC104##

This carboxylic acid was produced as described in Example 39 B.1 from7.7 parts by weight of 2,6-dichloro-C-phenylglycine and 6.8 parts byweight of 1-chlorocarbonyl-3-methylsulphonyl-imidazolid-2-one.

Melting point: > 260° C

Yield: 69%

IR-bands at 3400-2200, 3290, 1742, 1714, 1646, 1580, 1522 1260, 1170,1130, 783 and 763 cm⁻ ¹ (in Nujol).

NMR-signals at τ = 0.9 (h), 2.4-2.65(3H), 3.4 (1H), 5.8-6.2 (4H) and6.65 ppm (3H).

6. L(+)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid: ##SPC105##

This carboxylic acid was produced as described in Example 39 B.1 from5.0 parts by weight of L(+)-C-phenylglycine and 5.7 parts by weight of1-chlorocarbonyl-3-acetylimidazolid-2-one.

Melting point = 214° C

Yield: 69%

Calculated: C,55.0; H, 4.9; N, 13.8.

Found C(53.5); H, 5.2; N, 13.7.

IR-bands at 3650-2250, 3300, 1735, 1665 and 1252 cm⁻ ¹ (in Nujol).

NMR-signals at τ= 1.0 (1H), 2.3-2.8 (5H), 4.5 (1H), 6.2 (4H) and 7.6 ppm(3H).

7.D,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-phenylaceticacid: ##SPC106##

This carboxylic acid was produced as described in Example 39 B.1 from6.2 parts by weight of D,L-4-chloro-C-phenylglycine and 5.7 parts byweight of 1-chlorocarbonyl-3-acetyl-imidazolid-2-one.

Melting point: 194° C

Yield: 53%

Calculated: C, 49.5; H, 4.1; Cl, 10.4; N, 12.4.

Found: C, 49.6; H, 4.6; Cl, 9.4; N, 12.2.

IR-bands at 3700-2300, 3290, 1725, 1685, 1648 and 1252 cm⁻ ¹ (in Nujol).

NMR signals at τ = 0.9 (1H, 2.55 (4H), 4.45 (1H), 6.2 (4H) and 7.55 ppm(3H).

8.D,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid: ##SPC107##

This carboxylic acid was produced as described in Example 39 B.1 from5.4 parts by weight of 4-methyl-C-phenylglycine and 5.7 parts by weightof 1-chlorocarbonyl-3-acetylimidazolid-2-one.

Yield: 42%

IR-bands at 3600-2200, 3310, 1738, 1712, 1678, 1666 and 1256 cm⁻ ¹ (inNujol).

NRM-signals at = 1.0 (1H), 2.6 (2H), 2.8 (2H), 4.5 (1H), 6.2 (4H), 7.6(3H) and 7.7 ppm (3H) (in acetone-d₆).

9.D,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl-(2)-aceticacid: ##SPC108##

This carboxylic acid was produced as described in Example 39 B.1 from8.6 parts by weight of thienyl-(2)-acetic and 9.5 parts by weight of1-chlorocarbonyl-3-acetyl-imidazolid-2-one.

Melting point 197° C

Yield: 62%

Calculated: C, 46.3; H, 4.2; N, 13.5; S, 10.3.

Found: C, 47.1; H, 4.4; N, 13.8; S, 9.7.

IR-bands at 3280, 3080, 3450-2300, 1728, 1680, 1652, 1522, 1260 and 705cm⁻ ¹ (in Nujol).

NMR-signals at τ = 1.1 (1H), 2.5-3.2 (3H), 4.2 (1H), 6.2 (4H) and 7.6ppm (3H).

10.D,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-2,6-dichloro-phenylaceticacid: ##SPC109##

This carboxylic acid was produced as described in Example 39 B.1 from6.7 parts by weight of 2,6-dichloro-C-phenylglycine and 5.3 parts byweight of 1-chlorocarbonyl-3-acetyl-imidazolid-2-one.

Melting point: = 250° C

Yield: 74%

Calculated: C, 44.9; H, 3.5; Cl, 19.0; N, 11.2.

Found: C, 45.2; H, 3.7; Cl, 18.5; N, 11.4.

IR-bands at 3600-2200, 3302, 1735, 1682, 1625, 1520 and 1255 cm⁻ ¹ (inNujol).

NMR-signals at τ = 0.7 (1H), 2.3-2.7 (3H), 3.4 (1H), 6.2 (4H) and 7.6ppm (3H).

C. 1-Chlorocarbonyl-3-methylsulphonyl-imidazolidone-(2) ##SPC110##

16.4 parts by weight of 1-methylsulphonyl-imidazolidone-(2) in dioxanewere boiled for 3 days with 27 parts by weight of trimethylchlorosilaneand 20 parts by weight of triethylamine. The triethylamine hydrochloridewhich had precipitated was filtered off, 11 parts by weight of phosgenewere added and the mixture was left to stand overnight at roomtemperature. Thereafter it was evaporated to dryness and the product wasrecrystallized from boiling acetone.

Yield 70 %.

Melting point = 178° C

Calculated: C, 26.5; H, 3.1; Cl, 15.7; N, 12.4; S, 14.1.

Found: C, 27.2; H, 3.4; Cl, 15.3; N, 12.0; S, 14.1.

NMR-signals at τ = 5.6 - 6.2 (4H), and 6.6 ppm (3H).

IR-bands at 3010, 1807, 1721, 1360, 1165, 984 and 742 cm⁻ ¹.

The same product can also be advantageously produced from1-methylsulphonyl-imidazolid-2-one and excess phosgene in methylenechloride in the presence of pyridine.

D. N-methylsulphonyl-imidazolid-2-one: ##SPC111## Instructions 1

63 parts by weight of methanesulphochloride were added dropwise at roomtemperature to a suspension of 43 parts by weight of imidazolid-2-one in400 parts by volume of dry tetrahydrofurane and the mixture was stirredfor 1 hour at 30°-40° C and then heated for 1 hour under reflux.Thereafter, the solvent was distilled off in vacuo and the residue waskept for 1 hour at 60° C, under an oil pump. The residue wasrecrystallized from warm acetone.

Yield: 25%

Melting point = 193° C

Calculated: C, 29.3; H, 4.9; N, 17.1; S, 19.5.

Found: C, 29.0; H, 5.0; N, 17.2; S, 19.6.

IR-bands at 3250, 3115, 1715, 1350 and 1160 cm⁻ ¹.

NMR-signals at τ = 2.4 (1H), 6.2 (2H), 6.5 (2H), and 6.8 ppm (3H).

Instructions 2

80 parts by weight of methanesulphochloride, followed by 56 parts byweight of triethylamine, were added dropwise over the course of 30minutes to a suspension of 43 parts by weight of imidazolid-2-one in 300parts by volume of dry tetrahydrofurane, in such a way that the internaltemperature was about 35°-40° C. The mixture was stirred for a further 2hours at 45° C, the solvent was then stripped off in vacuo, the residuewhich remained was twice extracted with 150 parts by volume ofchloroform at a time and the crystals which remained were recrystallizedfrom methanol.

yield: 49%. According to the melting point and IR-spectrum, the productagrees with the N-methylsulphonylimidazolid-2-one described above.

EXAMPLE 40 SodiumD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorobenzylpenicillin:##SPC112##

This penicillin was produced as described in Example 39A from 7.5 partsby weight ofD,L-α[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorophenylacetic acid, 3.75 parts by weight of tetramethylchloroformamidiniumchloride and 4.7 parts by weight of 6-aminopenicillanic acid. Instead ofN-methylmorpholine, 2.02 parts by weight of triethylamine were used.

Yield: 65%

β-Lactam content: 62%

According to the NMR-spectrum, the product still contained 24% ofmethylsulphonylimidazolidonyl-carbonylaminochlorophenyl-acetic acidwhich was, however, removable by fractional acidification of the aqueoussolution of the penicillin sodium salt.

IR-bands at 3310, 1760, 1722, 1670, 1605 and 1170 cm⁻ ¹ (in Nujol).

NMR-signals at τ = 2.53 (2H), 2.67 (2H), 4.4 (1H), 4.5 (2H), 5.8 (1H),6.1 (4H), 6.65 (3H) and 8.3- 8.5 ppm (6H), (in methanol d₄).

EXAMPLE 41 SodiumD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl-(2)-methylpenicillin:##SPC113##

This penicillin was produced as described in Example 39A from 7.0 partsby weight ofD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl(2)-aceticacid, 3.75 parts by weight of tetramethylchloroformamidinium chlorideand 4.8 parts by weight of 6-aminopenicillanic acid.

Yield: 38%

β-Lactam content: 68%

IR-bands at 3310, 1758, 1722, 1650, 1605 and 1170 cm⁻ ¹.

NMR-signals at τ = 2.5-3.1 (3H), 4.1-4.6 (3H), 5.8 (1H), 6.1 (4H), 6.7(3H) and 8.25-8.5 ppm (6H).

The crude product still contained about 30% of sodiumD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl-(2)-acetate,which was, however, removable by fractional acidification of the aqueoussolution.

EXAMPLE 42 SodiumL(+)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC114##

This penicillin was produced as described in Example 39 A from 6.8 partsby weight ofL(+)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid, 3.75 parts by weight of tetramethylchloroformamidinium chlorideand 4.7 parts by weight of 6-aminopenicillanic acid.

Yield: 72%

β-Lactam content: 66%

Calculated: C, 44.1; H, 4.7; N, 11.5; S, 10.6.

Found: C, 43.5; H, 5.5; N, 11.5; S, 10.1.

In calculating the analytical values, a water content of 3% and a sodium2-ethylhexanoate content of 2% were taken into account.

IR-bands at 3310, 1760, 1722, 1665, 1602 and 1168 cm⁻ ¹.

NMR-signals at τ = 2.6 (5H), 4.35-4.8 (3H), 5.8 (1H), 6.2 (4H), 6.7 (3H)and 8.4 ppm (6H).

EXAMPLE 42 SodiumD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-2,6-dichloro-benzylpenicillin:##SPC115##

This penicillin was produced as described in Example 39 A from 7.0 partsby weight ofD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-2,6-di-chlorophenylacetic acid, 3.2 parts by weight of tetramethylchloroformamidiniumchloride and 4.3 parts by weight of 6-aminopenicillanic acid.

However, the reaction of the substituted phenylacetic acid with thetetramethylchloroformamidinium chloride was not carried out at -40° C,as in Example 39 A, but at -2.° C.

Yield: 77%

β-Lactam content: 61.5%

Calculated: C, 38.5; H, 4.0; Cl, 12.2; N 10.0; S 8.7.

Found: C, 36.0; H, 4.0; Cl, 12.6; N, 10.5; S, 9.3.

IR-bands at 3310, 1764, 1720, 1678, 1607, 1512, 1255 and 1167 cm⁻ ¹ (inNujol)

NMR-signals at τ = 2.5-2.9 (3H), 3.8 (1H), 4.45 (2H), 5.8 (1H), 6.15(4H), 6.7 (3H) and 8.3- 8.6 ppm (6H).

In calculating the analytical values, a content of 62% of penicillin,30% of sodiumα-[(3-methylsulphonylimidazolidin-2-on-1-yl)-carbonylamino]-2,6-dichloro-phenylacetate,4.0% of sodium 2-ethylhexanoate and 3.6% of water was used as the basis.These contents follow from the NMR-spectrum of the crude product. Thepenicillin can be obtained in the pure form by fractional acidificationof the aqueous solution of the crude product.

EXAMPLE 44 A. SodiumL(+)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC116##

This penicillin was produced as described in Example 39A from 5.0 partsby weight ofL(+)-α-[(3-acetylimidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid, 3.1 parts by weight of tetramethylchloroformamidinium chloride and4.3 parts by weight of 6-aminopenicillanic acid.

Yield: 74%

β-Lactam content: 75%

IR-bands at 3305, 1765, 1730, 1675, 1605, 1520 and 1258 cm⁻ ¹ (inNujol).

NMR-signals at τ = 2.4-2.8 (5H), 4.5- 4.8 (3H), 5.8 (1H), 6.22 (4H), 7.5(3H) and 8.5 ppm (6H).

B. 3-Acetyl-imidazolidin-2-on-1-carbonyl chloride ##SPC117##

20 parts by weight of N-acetyl-imidazolidone-2 mixed with 25 parts byweight of triethylamine and 150 parts by volume of dry benzene wereinitially taken and 27 parts by weight of trimethylchlorosilane in 40parts by volume of benzene were added dropwise over the course of 30minutes at room temperature, with stirring. Thereafter, the mixture wasboiled for 18 hours under reflux with exclusion of moisture, and aftercooling the triethylamaine hydrochloride which had precipitated (22parts by weight = 100%) was filtered off and carefully eluted with drybenzene. The benzene solution thus obtained was treated, at 5° C, with asolution of 17 parts by weight of phosgene in 50 parts by volume ofbenzene and left to stand overnight at 5° C. Thereafter, the solvent wasstripped off in vacuo and the residue was dried under an oil pump. Itwas recrystallized from an acetone/pentane mixture.

Yield: 81%

Melting point = 104° C

Calculated: C,37.7; H, 3.7; Cl, 18.6; N, 14.7.

Found: C, 39.3; H, 4.3; Cl, 17.7; N, 14.7.

IR-bands at 1798, 1740, 1690, and 1660 cm⁻ ¹.

NMR-signals at τ = 5.65-6.3 (4H) and 7.45 ppm (3H)

According to the NMR-spectrum, the product still contained 5 - 10% ofN-acetyl-imidazolone, which however does not interfere in the reactionwith C-phenylglycine and other amino-acids (as in Example 39, B6).

C. N-acetyl-imidazolid-2-one ##SPC118##

23.6 parts by weight of acetyl chloride in 100 parts by volume oftetrahydrofurane were added dropwise over the course of 60 minutes, at0° C, to a suspension of 25.8 parts by weight of imidazolone-2 in 350parts by volume of dry tetrahydrofurane. The mixture was stirred for 3hours at room temperature and dry air was subsequently blown through thesolution for some time; the solvent was then recovered in vacuo and theresidue was recrystallized from boiling nitromethane.

Yield: 52%

Melting point 188° C.

Calculated: C, 46.9; H, 6.9; N, 21.9.

Found: C, 47.0; H, 6.2; N, 22.5.

IR-bands at 3230, 1730 and 1640 cm⁻ ¹.

NMR-signals at τ = 6.2 (2H), 6.5 (2H), and 7.6 ppm (3H)

EXAMPLE 45 SodiumD,L-α-[(3-acetylimidazolidin-2-on-1-yl)-carbonyl-amino]-4-chlorobenzylpenicillin:##SPC119##

This penicillin was produced as described in Example 39A from 4.0 partsby weight ofD,L-α-[(3-acetylimidazolidin-2-on-1-yl)-carbonylamino]-5-chlorophenylaceticacid, 2.2 parts by weight of tetramethylchloroformamidinium chloride and3.25 parts by weight of 6-aminopenicillanic acid.

Yield: 76%

β-Lactam content: 89%

IR-bands at 3310, 1760, 1730, 1670, 1600, 1518 and 1259 cm⁻ ¹ (inNujol).

NMR-signals at τ = 2.4-2.9 (4H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.2 (4H),7.5 (3H), and 8.3-8.5 ppm (6H).

EXAMPLE 46 SodiumD,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-benzylpenicillin:##SPC120##

This penicillin was produced as described in Example 39A from 3.2 partsby weight ofD,L-α-[(3-acetylimidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid, 1.9 parts by weight of tetramethylchloroformamidinium chloride and2.6 parts by weight of 6-aminopenicillanic acid.

Yield: 45%

β-Lactam content: 83%

IR-bands at 3305, 1760, 1725, 1672, 1600, 1515 and 1255 cm⁻ ¹ (inNujol).

NMR-signals at τ = 2.6-2.8 (4H), 4.4-4.8 (2H), 5.8 (1H), 6.2 (4H), 7.5(3H), 7.7 (3H) and 8.3-8.6 ppm (6H)

EXAMPLE 47 SodiumD,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl-(2)-methylpenicillin##SPC121##

This penicillin was produced as described in Example 39A from 8 parts byweight ofD,L-α-[(3-acetylimidazolidin-2-on-1-yl)-carbonylamino]-thienyl-(2)-aceticacid, 4.9 parts by weight of tetramethylchloroformamidinium chloride and6.5 parts by weight of 6-aminopenicillanic acid.

Yield: 88%

β-Lactam content: 87%

IR-bands at 3302, 1760, 1732, 1678, 1605, 1520, 1315 and 1261 cm⁻ ¹ (inNujol).

NMR-signals at τ = 2.5-3.2 (3H), 4.0-4.5 (3H), 5.8 (1H), 6.2 (4H), 7.5(3H) and 8.2-8.6 ppm (6H).

EXAMPLE 48 SodiumD,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-2.6-dichloro-benzylpenicillin##SPC122##

This penicillin was produced as described in Example 39A from 6.5 partsby weight ofD,L-α-[(3-acetylimidazolidin-2-on-1-yl)-carbonylamino]-2,6-dichlorophenylaceticacid, 3.2 parts by weight of tetramethylchloroformamidinium chloride and4.3 parts by weight of 6-aminopenicillanic acid. The reaction of thesubstituted phenylacetic acid with the tetramethyl-chloroformamidiniumchloride was carried out at -10° C.

Yield: 29%

β-Lactam content: 66%

IR-bands at 3310, 1765, 1735, 1685, 1615, 1520, 1265, 1100, 1028 and 805cm⁻ ¹ (in Nujol).

NMR-signals at = 2.7 (3H), 3.8 (1H), 4.3-4.6 (2H), 5.8 (1H), 6.2 (4H),7.5 (3H) and 8.2-8.6 ppm (6H).

According to the NMR-spectrum, the crude product contained 27% of sodiumD,L-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-2,6-dichloro-phenylacetate,which is removable from the product by fractional acidification of theaqueous solution.

EXAMPLE 49 SodiumD(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin##SPC123##

2.9 parts by weight ofD(-)-α-[(3-ethylsulphonylimidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid (the substance contained 1 mol of isopropanol and 1 mol of H₂ O onthe crystal) were dissolved in 30 parts by volume of tetrahydrofurane.The solution was then cooled to -30° C and combined with a solution,cooled to -40° C, of 1.6 parts by weight oftetramethylchloroformamidinium chloride in 30 parts by volume ofdichloromethane. Therearter the mixture was brought to -25° C, and 0.9part by weight of N-methylmorpholine were added followed, after 3minutes, by a mixture, cooled to -5° C, of 2.3 parts by weight of6-aminopenicillanic acid and 25 parts by volume of 90% strength aqueoustetrahydrofurane, which was adjusted to pH 2.5 with approximately 10%strength hydrochloric acid. Thereafter the temperature was allowed torise to 0° C and the pH of the mixture was kept at 2.5 by appropriateaddition of N-methylmorpholine or dilute sodium hydroxide solution.After 1 hour, no further addition of base was necessary to maintain thepH of 2.5. The mixture was then adjusted to pH 7.0, the bulk of thetetrahydrofurane was removed in vacuo and the remaining aqueous phasewas extracted once by shaking with ether (the ether phase beingdiscarded), covered with ether-ethylacetate mixture and acidified to pH1.5. The organic phase was separated off, washed with water and driedfor 1 hour over MgSO₄ at 0° C. The drying agent was then removed and thesodium salt of the penicillin was precipitated with a solution of sodium2-ethylhexanoate in ether containing methanol.

Yield: 3.2 parts by weight

β-Lactam content: 81.9%

NMR-signals at τ = 2.4-2.85 (5H), 4.4-4.8 (3H), 5.8 (1H), 6.15 (4H),6.3-6.7 (2H) and 8.3-8.8 ppm (9H).

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid: ##SPC124##

4.5 parts by weight of 3-ethylsulphonyl-imidazolidin-2-one-1-carbonylchloride were added at about 0° C to a solution of 5.5 parts by weightof D(-)-bis-trimethylsilyl-α-aminophenyl-acetic acid in 40 parts byvolume of tetrachloromethane. The mixture was then left to stand for 4hours at 20° C; the solvent was then stripped off and the residue wasthoroughly worked with 1 N HCl in a mortar. The solid product wasfiltered off, washed with water, dried and recrystallized fromisopropanol.

Yield: 6.0 parts by weight.

Melting point = 102° (re-solidifies, and then:) melting point = 211°(heating bench).

The content of 1 mol of isopropanol and 1 mol of H₂ O was taken intoaccount in the calculated analytical data.

Calculated: C, 47.1, H, 6.3; N, 9.7; S, 7.4

Found: C, 47.1; H, 5.7; N, 9.7; S, 7.6

NMR-signals at τ = 2.6 (5H), 4.6 (1H), 6.1 (4H), 6.3-6.7 (2H) and8.5-8.7 ppm (3H).

3-Ethylsulphonyl-imidazolidin-2-one-1-carbonyl chloride ##SPC125##

This product was produced from 3-ethylsulphonyl-imidazolidin-2-one andphosgene in dichloromethane and in the presence of pyridine, at 20° C.

Melting point = 174°

Calculated: C, 29.9; H, 3.8; Cl, 14.8; N, 11.6; S, 13.3.

Found: C, 30.1; H, 3.8; Cl, 14.7; N, 11.8; S, 13.3.

NMR-signals at τ = 5.5-6.1 (4H), 6.2-6.65 (2H) and 8.4-8.75 ppm (3H).

1-Ethylsulphonyl-imidazolidin-2-one ##SPC126##

This substance was obtained by heating molar amounts ofimidazolidin-2-one and ethylsulphonyl chloride at 150° to 180° (untilthe evolution of HCl had ceased). The pure substance was isolated byextraction with hot benzene, acetone and ethyl acetate from the crudeproduct, and recrystallization from acetone (with addition of activecharcoal).

Melting point = 114°

Calculated: C, 33.7; H, 5.7; N, 15.7; S, 18.0.

Found: C, 33.1; H, 5.7; N, 16.3; S, 17.7.

NMR-signals at τ = 5.9-6.7 (6H) and 8.5-8.8 ppm (3H).

EXAMPLE 50 SodiumD(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:##SPC127##

A solution of 8.6 parts by weight ofD(-)-bis-trimethyl-silyl-α-aminophenylacetic acid in dichloromethane wascooled to 0° C, a solution of 7.0 parts by weight of3-ethylsulphonyl-imidazolidin-2-one-1-carbonyl chloride in 15 parts byvolume of dichloromethane was then added dropwise with further cooling,and the mixture was subsequently left to stand overnight at 0° C. Asolution of 5.0 parts by weight of tetramethylchloroformamidiniumchloride in 15 parts by volume of dichloromethane was then added and themixture was left to stand for 1 hour at 0° C. This reaction mixture wasthen introduced dropwise into a suspension, cooled to 0° C and adjustedto pH 2.5 with dilute hydrochloric acid, of 8.2 parts by weight of6-aminopenicillanic acid in 85 parts by volume of 80% strength aqueoustetrahydrofurane and at the same time the pH was kept at 2.5 byappropriate addition of dilute NaOH. The mixture was then stirred for afurther hour at 0° C and during stirring the pH was kept at 2.5 byfurther addition of dilute sodium hydroxide solution where necessary,.The pH was now adjusted to 7.0, the volatile organic solvents wereremoved in vacuo and the sodium salt of the penicillin was isolated inthe manner described in the preceding example.

Yield: 8.0 parts by weight

β-Lactam content: 58%

EXAMPLE 51 Sodiumα-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin:##SPC128##

This penicillin was produced as described in Example 49 from 4.5 partsby weight ofα-[(3-ethyl-sulphonylimidazolidin-2-on-1-yl)-carbonylamino]-p-chlorophenylaceticacid, 2.3 parts by weight of tetramethylchloroformamidinium chloride,1.3 parts by weight of N-methylmorpholine and 3.2 parts by weight of6-aminopenicillanic acid. However, the coupling with 6-aminopenicillanicacid was effected not aftr 3 minutes but after 6 minutes.

Yield: 4.4 parts by weight

IR-bands at 3300, 1765, 1725, 1670, 1600, 1500-1520, 1260, 1165, 1130cm⁻ ¹ (Nujol).

α[(3-Ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorophenylaceticacid: ##SPC129##

Sufficient concentrated sodium hydroxide solution just to dissolve theacid was added to a suspension of 11.0 parts by weight ofp-chloro-α-aminophenylacetic acid in 110 parts by volume of 50% strengthaqueous dioxane. Dilute hydrochloric acid was then added with stirringuntil a pH of 7.5-8.0 was reached. 13.0 parts by weight of3-ethylsulphonyl-imidazolidin-2-one-1-carbonyl chloride were then addedin portions at about 0° C and the pH of the mixture was maintained at7.5-8.0 by means of dilute sodium hydroxide solution. Thereafter themixture was stirred further for as long as an occasional addition ofsodium hydroxide solution was still necessary to maintain the pH of7.5-8.0. .sup.≲The bulk of the dioxane was then removed in vacuo at pH6.5, about 200 parts by volume of water were added, the mixture wasextracted once with ether at pH 9.0 (the ether extract being discarded)and covered with fresh ether, and the pH was brought to 0.5 withstirring. The organic phase was then separated off, washed, dried andcompletely evaporated in vacuo. The residue was dissolved in hot ethylacetate; thereafter the same amount of benzene and petroleum ether wasadded until there is turbidity which (only just) disappears again, andthe mixture was left to crystallize.

Yield: 4.9 parts by weight.

Melting point = 168° C

NMR-signals at τ = 2.6 (4H), 4.6 (1H), 6.1 (4H), 6.3-6.7 (2H) and8.4-8.8 ppm (3H).

IR-bands at 3300, 1720, 1650, 1540, 1350 and 1160 cm⁻ ¹ (Nujol).

EXAMPLE 52

If, in the manner described in Example 39A 0.02 mol of:

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorophenylaceticacid,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitrophenylaceticacid,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxyphenylaceticacid,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-thienyl-(2)-aceticacid,

D,l-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-phenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorophenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-phenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-yl)-carbonylamino]-4-nitrophenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-yl)-carbonylamino]-4-hydroxyphenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-yl)-carbonylamino]-thienyl-(2)-aceticacid,

D,l-α-[(3-ethylsulphonyl-imidazolidin-2-on-yl)-carbonylamino]-4-methylsulphonyl-phenylaceticacid,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorophenylaceticacid,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitrophenylaceticacid,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxyphenylaceticacid,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-thienyl-(2)-aceticacid,

D,l-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-phenylaceticacid,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorophenylaceticacid,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitrophenylaceticacid,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxyphenylaceticacid,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-thienyl-(2)-aceticacid,

D,l-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-phenylaceticacid,

D(-)-α-[(3-furoyl-(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorophenylaceticacid,

D(-)-α-[(3-furoyl-(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid,

D(-)-α-[(3-furoyl-(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitrophenylaceticacid,

D(-)-α-[(3-furoyl-(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxyphenylaceticacid,

D(-)-α-[(3-furoyl-(2)-imidazolidin-2-on-1-yl)-carbonylamino]-thienyl-(2)-aceticacid,

D,l-α-[(3-furoyl-(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-phenylaceticacid,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorophenylaceticacid,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylaminio]-4-nitrophenylaceticacid,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxyphenylaceticacid,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-thienyl-(2)-aceticacid, or

D,l-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-phenylaceticacid

is reacted with 0.02 mol of tetramethylchloroformamidinium chloride and0.022 mol of 6-aminopenicillanic acid, the following penicillins areobtained in the form of their sodium salts:

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitro-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxy-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl-(2)-methylpenicillin,

D,l-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitro-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxy-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl-(2)-methylpenicillin,

D,l-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-benzylpenicillin,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-benzylpenicillin,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-benzylpenicillin,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitro-benzylpenicillin,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxy-benzylpenicillin,

D(-)-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl-(2)-methylpenicillin,

D,l-α-[(3-acetyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-benzylpenicillin,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-benzylpenicillin,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-benzylpenicillin,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitro-benzylpenicillin,

D(-)-α-[(3-formylimidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxy-benzylpenicillin,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl-(2)-methylpenicillin,

D,l-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-benzylpenicillin,

D(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-benzylpenicillin,

D(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-benzylpenicillin,

D(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitro-benzylpenicillin,

D(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxy-benzylpenicillin,

D(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,

D,l-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-benzylpenicillin,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-benzylpenicillin,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1yl)-carbonylamino]-4-methyl-benzylpenicillin,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-nitro-benzylpenicillin,D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-hydroxy-benzylpenicillin,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,or

D,l-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylsulphonyl-benzylpenicillin.

EXAMPLE 53

If, as described in Example 39A 0.02 mol of

D(-)-α-[(3methylaminocarbonyl-imidazolidin-2-on-1-yl)carbonylamino]-phenylaceticacid,

D(-)-α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-dimethylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propyloxycarbonyl-imidazolidin-2-on-1-yl)carbonylamino]-phenylaceticacid,

D(-)-α-[(3-pyrrolid-1-yl-carbonyl-imidazolidin-2-on-1-yl)carbonylamino]-phenylaceticacid,

D(-)-α-[(3-piperid-1-yl-carbonyl-imidazolidin-2-on-1-yl)carbonylamino]-phenylaceticacid,

D(-)-α-[(3-phenylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-n-butyryl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(2-methylsulphonylamino-4,5-dihydro-imidazol-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]phenylaceticacid,

D(-)-α-[(3-pivaloyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-ethoxycarbonylamino-sulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-cyclohexyloxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylacetic acid,

D(-)-α-[(3-methylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid or

D(-)-α-[3-methylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid

is reacted with 0.02 mol of tetramethylchloroformamidinium chloride andsubsequently with 0.022 mol of 6-aminopenicillanic acid, the followingpenicillins are obtained in the form of their sodium salts:

D(-)-α-[(3-methylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-aminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-dimethylaminocarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propyloxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-pyrrolid-1-yl-carbonyl-imidazolidin-2-on-1-yl)carbonylamino]-benzylpenicillin,

D(-)-α-[(3-piperidid-1-yl-carbonyl-imidazolidin-2-on-1-yl)carbonylamino]-benzylpenicillin,

D(-)-α-[(3-phenylaminocarbonyl-imidazolidin-2-on-1-yl)carbonylamino]-benzylpenicillin,

D(-)-α-[(3-phenoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-benzoyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-furoyl(2)-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-butyryl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(2-methylsulphonylamino-4,5-dihydro-imidazol-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-pivaloyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-ethoxy-carbonylamino-sulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-cyclohexyloxycarbonyl-imidazolidin-2-on-1-yl)carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)carbonylamino]-benzylpenicillin,or

D(-)-α-[(3-methylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin.

EXAMPLE 54

If, as described in Example 39A 0.02 mol of

D(-)-α-(5-benzoyl-5-methyl-biureido)-phenylacetic acid,

D(-)-α-(5-benzoyl-5-methyl-2-thio-biureido)-phenylacetic acid,

D(-)-α-(5-acetyl-5-methyl-biureido)-phenylacetic acid,

D(-)-α-(5-acetyl-5-methyl-2-thio-biureido)-phenylacetic acid,

D(-)-α-[3-(imidazolidin-2-on-1-yl-carbonyl)-ureido]-phenylacetic acid,

D(-)-α-[3-imidazolidin-2-on-1-yl-carbonyl)-thioureido]-phenylaceticacid,

D(-)-α-(5-dimethylaminocarbonyl-5-methyl-biureido)-phenylacetic acid,

D(-)-α-(5-dimethylaminocarbonyl-5-methyl-2-thio-biureido)-phenylaceticacid,

D(-)-α-(5-methylsulphonyl-5-methyl-biureido)-phenylacetic acid,

D(-)-α-(5-methylsulphonyl-5-methyl-2-thio-biureido)-phenylacetic acid,

D(-)-α-(5-methylaminocarbonyl-5-methyl-biureido)-phenylacetic acid,

D(-)-α-(5-methylaminocarbonyl-5-methyl-2-thio-biureido)-phenylaceticacid,

D(-)-α-(5-furoyl(2)-5-methyl-biureido)-phenylacetic acid,

D(-)-α-(5-furoyl(2)-5-methyl-2-thio-biureido)-phenylacetic acid,

D(-)-α-[3-isothiazolidine-1,1-dioxid-2-yl-carbonyl)-ureido]-phenylaceticacid,

D(-)-α-[3-(isothiazolidine-1,1-dioxid-2-yl-carbonyl)-thioureido]-phenylaceticacid,

D(-)-α-[3-(pyrrolidin-2-on-1-yl-carbonyl)-ureido]-phenylacetic acid or

D(-)-α-(3-(pyrrolidin-2-on-1-yl-carbonyl)-thioureido]-phenylacetic acid

is reacted with 0.02 mol of tetramethylchloroformamidinium chloride and0.022 mol of 6-aminopenicillanic acid, the following penicillins areobtained in the form of their sodium salts:

D(-)-α-(5-benzoyl-5-methyl-biureido)-benzylpenicillin

D(-)-α-(5-benzoyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-(5-acetyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-acetyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-[3-(imidazolidin-2-on-1-yl-carbonyl)-ureido]-benzylpenicillin,

D(-)-α-[3-(imidazolidin-2-on-1-yl-carbonyl)-thioureido]-benzylpenicillin,

D(-)-α-(5-dimethylaminocarbonyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-dimethylaminocarbonyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-(5-methylsulphonyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-methylsulphonyl-5-methyl-thio-ureido)-benzylpenicillin,

D(-)-α-(5-methylaminocarbonyl-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-methylaminocarbonyl-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-(5-furoyl(2)-5-methyl-biureido)-benzylpenicillin,

D(-)-α-(5-furoyl(2)-5-methyl-2-thio-biureido)-benzylpenicillin,

D(-)-α-[3-(isothiazolidine-1,1-dioxide-2-yl-carbonyl)ureido]-benzylpenicillin,

D(-)-α-[3-(isothiazolidine-1,1-dioxide-2-yl-carbonyl)thioureido]-benzylpenicillin,

D(-)-α-[3-(pyrrolidin-2-on-1-yl-carbonyl)-ureido]-benzylpenicillin, or

D(-)-α-[3-(pyrrolidin-2-on-1-yl-carbonyl)-thioureido]-benzylpenicillin.

EXAMPLE 55

If, as described in Example 39A, 0.02 mol of

D(-)-α-[(3-propionyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-acetyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-acetyl-5-methyl-imidazolidin-2-on-1yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-acetyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-n-propylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)carbonylamino]-phenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-5-methyl-imidazolidin-2-on-1yl)carbonylamino]-phenylaceticacid,

D(-)-α-[(3-ethylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-n-propylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propysulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-n-propylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-n-propylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-phenylsulphonyl-imidazolidin-2-on-1yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-p-methylphenylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-cyclohexylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-thienyl(2)-sulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-formyl-4-methyl-imidazolidin-3-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-formyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-formyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methylaminocarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methylaminocarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methylaminocarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methoxycarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methoxycarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methoxycarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propyloxycarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propyloxycarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-i-propyloxycarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methylsulphonyl-4,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methylsulphonyl-4,4-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-methylsulphonyl-5,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-formyl-4,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid,

D(-)-α-[(3-formyl-4,4-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid or

D(-)-α-[(3-formyl-5,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid

is reacted with 0.02 mol of tetramethylchloroformamidinium chloride and0.022 mol of 6-aminopenicillanic acid, the followed penicillins areobtained in the form of their sodium salts:D(-)-α-[(3-propionyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,D(-)-α-[(3-acetyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-acetyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-acetyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,D(-)-α-[(3-ethylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-ethylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-4-methyl--imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propylsulphonyl-5-methyl--imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-n-propylsulphonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-phenylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-p-methylphenylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-cyclohexylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-thienyl(2)-sulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylaminocarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylaminocarbonyl-5-methyl-imidazolidin-2-on-1yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylaminocarbonyl-1,3-diaza-cyclohexan-2-on-1yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propyloxycarbonyl-4-methyl-imidazolidin-2-on-1yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propyloxycarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-i-propyloxycarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-4,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-4,4-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylsulphonyl-5,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-4,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-4,4-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-formyl-5,5-dimethyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylcarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,

D(-)-α-[(3-methylcarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillinor

D(-)-α-[(3-methylcarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin.

EXAMPLE 56 A. SodiumD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-benzylpenicillin:##SPC130##

This penicillin was produced as described in Example 39A from 7.0 partsby weight ofD,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methylphenylaceticacid, 3.8 parts by weight of tetramethylchloroformamidinium chloride and5.0 parts by weight of 6-aminopenicillanic acid.

Yield: 57%

β-Lactam content: 83%

IR-bands at 3320, 1765, 1727, 1674, 1605, 1515, 1255 and 1170 cm.sup.⁻¹(in Nujol).

NMR-signals at τ = 2.65 (2H), 2.83 (2H), 4.3-4.6 (3H), 5.8 (1H), 6.15(4H), 6.7 (3H), 7.7 (3H) and 8.3-8.6 ppm (6H).

B.D,L-α-[(3-methylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-methyl-phenylaceticacid: ##SPC131##

This carboxylic acid was produced as described in Example 39B.1 from11.3 parts by weight of1-chlorocarbonyl-3-methylsulphonyl-imidazolid-2-one and 9.1 parts byweight of D,L-α-4-(methylphenyl)-glycine.

Yield: 42%

IR-bands at 3700-2200, 3300, 1740-1660, 1540-1500, 1255 and 970cm.sup.⁻¹ (in Nujol). NMR-signals at τ .sup.υ 1.3 (1H), 2.7 (4H), 4.7(1H), 6.2 (4H), 6.6 (3H) and 7.7 ppm (3H).

EXAMPLE 57 A. SodiumD,L-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chlorobenzylpenicillin:##SPC132##

This penicillin was produced as described in Example 39A from 9 parts byweight ofD,L-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-phenylaceticacid, 4.85 parts by weight of tetramethylchloroformamidinium chlorideand 6.5 parts by weight of 6-aminopenicillanic acid.

Yield: 80%

β-Lactam content: 85%

IR-bands at 3300, 3050, 1770, 1742, 1730, 1670, 1605, 1520, 1320 and1260 cm.sup.⁻¹ (in Nujol).

NMR-signals at τ = 2.57 (2H), 2.65 (2H), 4.35-4.65 (3H), 6.14 (4H), 6.16(3H) and 8.3-8.6 ppm (6H).

B.D,L-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-4-chloro-phenylaceticacid:

This carboxylic acid was produced as described in Example 39B.1 from10.4 parts by weight of1-chlorocarbonyl-3-methoxycarbonyl-imidazolid-2-one and 10.2 parts byweight of D,L-α-(4-chlorophenyl)-glycine.

Yield: 61%

Calculated: C, 47.2; H, 4.0; Cl, 10.0; N, 11.8.

Found: C, 47.4; H, 4.5; Cl, 9.2; N, 11.2.

IR-bands at 3700-2250, 3280, 3060 and 1780-1630 cm.sup.⁻¹ (in Nujol).

NMR-signals at τ = 1.0 (1H), 2.5 (4H), 4.5 (1H), 6.15 (4H) and 6.20 ppm(3H).

C. 1-Chlorocarbonyl-3-methoxycarbonyl-imidazolid-2-one ##SPC133##

This carbamic acid chloride was produced as described in Example 45Bfrom 8 parts by weight of N-methoxycarbonyl-imidazolid-2-one, 9.7 partsby weight of trimethylchlorosilane, 9 parts by weight of triethylamineand 6.2 parts by weight of phosgene.

Yield: 72%

Melting point = 129° C

Calculated: C, 34.8; H, 3.4; Cl, 17.2; N, 13.6.

Found: C, 34.8; H, 3.4; Cl, 17.1; N, 13.6.

IR-bands at 1820, 1737, 1690 and 1260 cm.sup.⁻¹.

NMR-signals at τ = 5.7-6.3 (4H) and 6.1 ppm (3H).

D. N-methoxycarbonyl-imidazolid-2-one ##SPC134##

14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one wereintroduced into 70 parts by volume of ice-cold methanol and the mixturewas stirred for 1 hour at room temperature and subsequently for 1 hourat 40°-50° C. After stripping off the excess methanol, the product wasrecrystallized from acetone.

Yield: 55%

Melting point = 185° C.

Calculated: C, 41.6; H, 5.5; N, 19.4.

Found: C, 41.8; H, 4.8; N, 19.2.

IR-bands at 3320, 1745, and 1670 cm.sup.⁻¹.

EXAMPLE 58 A. SodiumD,L-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl(2)-methylpenicillin:##SPC135##

This penicillin was produced as described in Example 39A from 8.5 partsby weight ofD,L-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl(2)-aceticacid, 5.1 parts by weight of tetramethylchloroformamidinium chloride and6.9 parts by weight of 6-aminopenicillanic acid.

Yield: 72%

β-Lactam content: 67%

IR-bands at 3310, 1773, 1750, 1730, 1670, 1610, 1520, 1320 and 1265cm.sup.⁻¹ (in Nujol).

NMR-signals at = 2.5-3.2 (3H), 4.1 (1H), 4.4-4.6 (2H), 5.8 (1H), 6.15(7H) and 8.3-8.55 ppm (6H).

According to the NMR-spectrum, the crude product still contained 23% ofD,L-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl(2)-aceticacid, which is however removable by fractional acidification of theaqueous solution.

B.D,L-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-.alpha.-thienyl(2)-aceticacid: ##SPC136##

This carboxylic acid was produced as described in Example 39b. 1 from8.8 parts by weight of1-chlorocarbonyl-3-methoxycarbonyl-imidazolid-2-one and 7.3 parts byweight of D,L-α-thienyl(2)-glycine.

Yield: 73%

Calculated: C, 44.0; H, 4.0; N, 12.8; S, 9.8.

Found: C, 44.1; H, 4.0; N, 12.0; S, 9.9.

IR-bands at 3700-2200, 3280, 1775, 1740-1640, 1515 and 1015 cm.sup.⁻¹(in Nujol).

NMR-signals at τ = 0.9 (1H), 2.5-3.1 (3H), 4.2 (1H), 6.15 (4H) and 6.20ppm (3H).

EXAMPLE 59 SodiumD(-)-α-[(3-ethylsulphonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin:

2.9 parts by weight ofD(-)-α-[(3-ethylsulphonylimidazolidin-2-on-1-yl)-carbonylamino]-phenylaceticacid were dissolved in 30 parts by volume of tetrahydrofurane, thesolution was cooled to -30° C and a solution of 1.0 part by weight oftetramethylchloroformamidinium chloride in 30 parts by volume ofdichloromethane, pre-cooled to -30° C, was then added at once. Hereupon,some material precipitated. After the temperature had been allowed torise to -25° C to -20° C, a clear solution formed. This solution wasleft to stand for 15 minutes at -25° C. Then this solution was added allat once to a solution or suspension, maintained at 0° C to 5° C, of 2.3parts by weight of 6-aminopenicillanic acid in 25 parts by volume of 90%strength aqueous tetrahydrofurane which had been adjusted to pH 2.5 byadding 10% strength aqueous hydrochloric acid. Thereafter, the pH waskept at 2.5 by appropriate addition of 2 N aqueous sodium hydroxidesolution and the mixture was cooled with an ice-water mixture, as aresult of which the temperature was brought to 0° C, and kept there.After one hour the mixture was worked up, though in order to maintainthe pH of 2.5 it was still necessary to add sodium hydroxide solution,if only a little. Working up took place as described in Example 49.

Yield: 2.3 parts by weight

The IR-spectrum of this penicillin was identical to that of thepenicillin of Example 49.

What is claimed is:
 1. A compound selected from the group consisting ofa penicillin of the formula ##EQU17## wherein the carbon atom designatedby * constitutes a center of chirality; R₁ is alkoxy of 1 to 8 carbonatoms;each of X, Y and Z, independently of the others, is --CO-- or--CS--; B is thienyl, cyclohexenyl, cyclohexa-1,4-dien-1-yl, phenyl orphenyl substituted by one or two members selected from the groupconsisting of halo, nitro, hydroxy, methoxy, methylthio and alkyl of 1to 5 carbon atoms; and Q₁ is ethylene or trimethylene unsubstituted orsubstituted by one or two methyl groups;and the pharmaceuticallyacceptable salts thereof.
 2. A compound according to claim 1 whereineach of X and Y is --CO--.
 3. A compound according to claim 1 wherein Bis thienyl, cyclohexenyl, cyclohexa-1,4-dien-1-yl, phenyl, halophenyl,hydroxyphenyl, nitrophenyl, methoxyphenyl, methylphenyl, ormethylthiophenyl.
 4. A compound according to claim 1 whereineach of Xand Y is --CO--; B is thienyl, cyclohexenyl, cyclohexa-1,4-dien-1yl,phenyl, halophenyl or hydroxyphenyl; and Q₁ is ethylene or trimethylene,unsubstituted or substituted by one or two methyl groups.
 5. A compoundaccording to claim 1 wherein Z is --CO--.
 6. A compound according toclaim 1 wherein each of X, Y and Z is --CO--;B is phenyl; and Q isethylene, 1,2-propylene or trimethylene.
 7. A compound according toclaim 6 wherein Q is ethylene.
 8. A compound according to claim 1wherein the configuration about the carbon atom designated * is R.
 9. Acompound according to claim 1 wherein the configuration about the carbonatom designated * is S.
 10. A compound according to claim 4 which is analkali metal salt.
 11. A compound according to claim 4 which is thesodium salt.
 12. The compound according to claim 1 which isD(-)-α-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 13. The compound according to claim 1 whichis D(-)-α-[(3-i-propyloxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 14. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methoxybenzylpenicillin,or the sodium salt thereof.
 15. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylthiobenzylpenicillin,or the sodium salt thereof.
 16. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino-]-p-hydroxybenzylpenicillin,or the sodium salt thereof.
 17. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-chlorobenzylpenicillin,or the sodium salt thereof.
 18. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-nitrobenzylpenicillin,or the sodium salt thereof.
 19. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(2)-methylpenicillin,or the sodium salt thereof.
 20. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-α-thienyl(3)-methylpenicillin,or the sodium salt thereof.
 21. The compound according to claim 1 whichisD(-)-α-[(3-methoxycarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 22. The compound according to claim 1 whichisD(-)-α-[(3-methoxy-carbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 23. The compound according to claim 1 whichisD(-)-α-[(3-methoxycarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 24. The compound according to claim 1 whichisD(-)-α-[(3-i-propyloxycarbonyl-4-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 25. The compound according to claim 1 whichisD(-)-α-[(3-i-propyloxycarbonyl-5-methyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 26. The compound according to claim 1 whichisD(-)-α-[(3-i-propyloxycarbonyl-1,3-diaza-cyclohexan-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 27. The compound according to claim 1 whichisD(-)-α-[(3-i-propyloxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-benzylpenicillin,or the sodium salt thereof.
 28. The compound according to claim 1 whichisα-[(3-methoxycarbonyl-imidazolidin-2-on-1-yl)-carbonylamino]-p-methylbenzylpenicillin,or the sodium salt thereof.